*Calcium* Hypercalcemia Hypo calcemia Tetany *IRON* Mucosal block theory Anemia Wilson disease Hemosiderosis Na+ and K+regulation in kidney Hypo and hyperNatremia Hypo and hyperkalemia Pseudo hypernatremia Ph regulation by renal + respiratory mechanism Anion gap significance Calculation High AG Mixed acid base disorder Compensatory mechanism Metabolic acidosis nd alkalosis Respiratory acidosis nd alkalosis Factors affecting enzyme activity and action fig 3.18 .19 .20 Substrate concentration Tempt ph Enzyme regulations or inhibition (part of regulation) :2 types long and short term regulations Induction example:- cyt p50 by barbuttarea and repression example:- heme synthesis Long terms covalent modification 3m Allosdtresic regulation -5m imp Ultra short cm Classification of enzymes Enzyme inhibitoion reversible:- competitive Non revereselble ;- non completivve 3.27 3.29 a b Difference between competitive and nkn completivve 3.27 3.29 Other name of suicide inhibition Isoenzyme - applied aspect atleast one Acute pancreatitis, MI hepatitis Cellular markers Regans enzyme MCQ Co enzyme nd co factors Co enzyme is a part of co factors What is tpp, atp, plp , biotin , folate , co Acyl tranfering?? MCQ Enzyme classification Glycolysis Gluconeogenisis :- from 4 non carb precursor 4 key enzymes GLUT 12, 4, SGlu T 1,2 Glycogen metabolism Fructose metabolism Hmp pathway + significance Polyol pathway of glucose Regulation of blood glucose Metabolism of alcohol Glycogen disorders Acute toxicity of alcohol Fatty liver Hunter syndrome Hurler syndrome Mucopoly saccharides Galactosemia Alpha fatty oxidation Beta oxidation Metabolism of propionyl co A De novo synthesis of fat Triglycerides synthesis Ketone body metabolism Ketolysis Ketosis summary diagram Causes of HyperCholesterol Steroids synthesis from cholesterol HDL, LDL chylomicrons metabolism Eicosanoids Aspirin Classification of phospho lipid Pufa significance ETC Osmotic theory Complex inhibitors Uncouplers Collagen synthesis, structure Function of proteglycans , glyco glycans Defination of ECM

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MBBS 1st Year Biochemistry - Complete Notes

SECTION 1: CALCIUM METABOLISM

Calcium - Normal Values & Distribution

Total serum calcium: 9-11 mg/dL (2.25-2.75 mmol/L)
50% ionized (active), 40% protein-bound (mainly albumin), 10% complexed
Corrected Ca = Measured Ca + 0.8 × (4 - serum albumin)

Regulation of Calcium

Three hormones regulate calcium:

Hormone	Source	Effect on Ca
PTH	Chief cells of parathyroid	↑ Ca (↑ bone resorption, ↑ renal reabsorption, ↑ 1,25-VitD)
Vitamin D (1,25-dihydroxycholecalciferol)	Kidney (1-hydroxylation)	↑ Ca (↑ gut absorption, ↑ bone resorption)
Calcitonin	Parafollicular C cells of thyroid	↓ Ca (↓ bone resorption)

Hypercalcemia

Causes (CHIMPANZEES mnemonic):

C - Cancer (most common cause in hospitalized patients - PTHrP)
H - Hyperparathyroidism (most common outpatient cause - primary HPT)
I - Immobility
M - Milk-alkali syndrome
P - Paget's disease
A - Addison's disease
N - Neoplasms
Z - Zollinger-Ellison
E - Excess Vitamin D
E - Excess Vitamin A
S - Sarcoidosis/Thiazides

Clinical features: "Bones, Stones, Groans, Psychic Moans"

Bones: bone pain, pathological fractures
Stones: renal calculi (calcium oxalate/phosphate)
Groans: nausea, vomiting, constipation, anorexia
Psychic Moans: confusion, psychosis, lethargy, coma

ECG: Shortened QT interval

Treatment: IV saline (first line) → bisphosphonates → calcitonin → dialysis

Hypocalcemia

Causes:

Hypoparathyroidism (post-thyroidectomy most common)
Vitamin D deficiency (rickets in children, osteomalacia in adults)
Pseudohypoparathyroidism (resistance to PTH - Albright hereditary osteodystrophy)
Hypomagnesemia (impairs PTH secretion)
Chronic renal failure (↓ 1-hydroxylation)

Clinical features:

Neuromuscular excitability - tetany, paresthesias, cramps
Chvostek's sign - facial twitch on tapping facial nerve
Trousseau's sign - carpal spasm with BP cuff inflated (more specific)
ECG: Prolonged QT interval
Cataracts, seizures, laryngospasm, bronchospasm

Tetany

Tetany = spontaneous repetitive firing of motor nerves due to hypocalcemia (or hypomagnesemia, alkalosis).

Mechanism: Low ionized Ca²⁺ → reduces threshold for nerve excitation → repetitive depolarization

Types:

Hypocalcemic tetany - low Ca²⁺
Alkalotic tetany - alkalosis reduces ionized Ca (more Ca binds albumin)
Hypomagnesemic tetany - Mg²⁺ required for PTH secretion

Signs: Chvostek, Trousseau, carpopedal spasm, laryngospasm, Erb's sign (+ve at 6mA)

SECTION 2: IRON METABOLISM

Iron in the Body

Total body iron: ~4g in males, ~2.5g in females
Distribution: Hemoglobin (65%), Ferritin/Hemosiderin (30%), Myoglobin (4%), Enzymes (1%)
Daily requirement: Men 1mg/day absorbed; Women 1.5mg/day; Pregnancy 3mg/day

Iron Absorption

Site: Duodenum and upper jejunum
Form absorbed: Fe²⁺ (ferrous) - Vitamin C helps reduce Fe³⁺ to Fe²⁺
Facilitated by: Vitamin C, gastric acid, meat
Inhibited by: Phytates, oxalates, tannins (tea), antacids, high pH

Steps:

Luminal Fe³⁺ reduced to Fe²⁺ by Duodenal Cytochrome b (Dcytb)
Fe²⁺ enters enterocyte via DMT-1 (divalent metal transporter-1)
Inside cell: stored as ferritin OR transferred to blood via Ferroportin
Fe²⁺ oxidized to Fe³⁺ by Hephaestin (ferroxidase)
Fe³⁺ binds Transferrin in blood (2 iron atoms per transferrin)

Mucosal Block Theory

After a large iron load, enterocytes become "saturated" with iron stored as ferritin
These iron-laden enterocytes block further iron absorption for 2-3 days (lifespan of enterocyte)
When enterocyte is shed, iron is lost in feces
Mechanism: Hepcidin (liver-produced, APR protein) downregulates ferroportin → reduces iron export from enterocytes → "mucosal block"
Hepcidin is the MASTER regulator of iron homeostasis

Hepcidin

Produced by liver in response to: iron overload, inflammation, infection
Hepcidin → binds ferroportin → internalization/degradation of ferroportin → iron trapped in enterocytes and macrophages
In iron deficiency: hepcidin falls → more ferroportin → more iron absorption

Transport and Storage

Transferrin: plasma transport protein; TIBC = total iron binding capacity
Ferritin: storage form (liver, spleen, bone marrow); reflects iron stores
Hemosiderin: insoluble, degraded ferritin - seen in iron overload
Normal values: Serum iron 60-150 μg/dL; Ferritin 12-300 ng/mL; TIBC 250-370 μg/dL
Transferrin saturation = (Serum Fe / TIBC) × 100 = normally 30%

Iron Deficiency Anemia (IDA)

Stages:

Iron depletion - Ferritin ↓, serum Fe normal
Iron-deficient erythropoiesis - Ferritin ↓↓, TIBC ↑, transferrin saturation ↓
Iron deficiency anemia - Hb ↓, microcytic hypochromic RBCs

Lab: ↓ Hb, ↓ MCV, ↓ MCH, ↓ serum iron, ↑ TIBC, ↓ ferritin, ↑ RDW

Clinical: Koilonychia (spoon nails), angular cheilitis, glossitis, Plummer-Vinson syndrome (web in esophagus)

Wilson Disease (Copper - for comparison)

AR disorder - ATP7B gene mutation (chromosome 13)
Impaired copper excretion into bile → accumulation in liver, brain, cornea, kidney
Kayser-Fleischer rings in cornea (gold-brown, pathognomonic)
Ceruloplasmin is low (but this is a plasma copper carrier, not iron!)
Hepatic: cirrhosis, fulminant hepatic failure
Neuropsychiatric: tremor, dysarthria, personality change
Treatment: D-penicillamine, zinc acetate, trientine

Hemosiderosis

Definition: Excess iron deposition (as hemosiderin) WITHOUT tissue damage
Hemochromatosis = iron overload WITH organ damage

Primary (Hereditary) Hemochromatosis:

AR, HFE gene mutation (C282Y most common)
Excessive iron absorption despite adequate stores
Deposits in: liver (cirrhosis), pancreas (bronze diabetes), heart (cardiomyopathy), joints, skin (bronze pigmentation), gonads
Classic triad: Cirrhosis + diabetes + bronze skin = "Bronze diabetes"
Diagnosis: Transferrin saturation >45%, ferritin markedly elevated, liver biopsy, HFE gene testing
Treatment: Phlebotomy (preferred), deferasirox/deferoxamine

SECTION 3: Na⁺ AND K⁺ REGULATION IN KIDNEY

Sodium Handling

Freely filtered at glomerulus; ~99% reabsorbed
Proximal tubule (PT): 67% reabsorbed (Na-glucose, Na-amino acid cotransporters; Na/H exchanger)
Loop of Henle (thick ascending limb): 25% - NKCC2 cotransporter (target of loop diuretics)
Distal convoluted tubule (DCT): 5% - NCC (thiazide target); regulated by aldosterone
Collecting duct: 3% - ENaC (aldosterone regulated); aquaporin-2 (ADH regulated)

Hormonal regulation:

Hormone	Source	Effect on Na	Effect on K
Aldosterone	Adrenal cortex (zona glomerulosa)	↑ reabsorption in CD	↑ excretion
ANP/BNP	Heart atria/ventricles	↓ reabsorption	-
ADH (vasopressin)	Posterior pituitary	↑ water reabsorption (not Na)	-

Potassium Handling

90% reabsorbed in PT and loop of Henle (passive, with Na)
Fine-tuned in collecting duct by aldosterone
Aldosterone → ↑ principal cell Na reabsorption → more negative lumen → K⁺ secreted
K⁺ is excreted by principal cells via ROMK channels
K⁺ is reabsorbed by intercalated cells via H/K-ATPase

Hyponatremia (Na⁺ < 135 mEq/L)

Classification by osmolality:

Hypotonic hyponatremia (most common type):
- Hypovolemic: Diarrhea, vomiting, diuretics, Addison's → ↑ ADH (appropriate)
- Euvolemic: SIADH, hypothyroidism, psychogenic polydipsia → ↑ ADH (inappropriate)
- Hypervolemic: CHF, cirrhosis, nephrotic syndrome → ↑ ADH (appropriate)
Isotonic hyponatremia (Pseudohyponatremia): Hyperlipidemia, hyperproteinemia (no real change in plasma Na)
Hypertonic hyponatremia: Hyperglycemia (glucose draws water → dilutes Na); mannitol

Symptoms: Headache, nausea, confusion, seizures, coma (severe)

Treatment:

Chronic/asymptomatic: fluid restrict (SIADH), treat underlying cause
Severe/symptomatic: Hypertonic saline (3%)
Danger: Overcorrect too fast → Central Pontine Myelinolysis (CPM/ODS)
Safe correction rate: ≤8-10 mEq/L per 24 hours

Pseudohypernatremia

Na appears falsely elevated in lab due to decreased water fraction in plasma
Actually rare - more common issue is pseudohyponatremia
Can occur with very high lipids/proteins if certain methods used
True hypernatremia = Na⁺ > 145 mEq/L

Hypernatremia (Na⁺ > 145 mEq/L)

Causes:

Water loss (insensible, diarrhea, DI - central/nephrogenic)
Sodium gain (hypertonic saline, hyperaldosteronism)
Inadequate intake

Clinical: Thirst, lethargy, seizures, brain hemorrhage (cerebral dehydration)

Treatment: Free water (oral or D5W IV); correct slowly (max 10-12 mEq/L per day)

Hypokalemia (K⁺ < 3.5 mEq/L)

Causes:

GI loss: vomiting, diarrhea
Renal loss: diuretics (loop, thiazide), hyperaldosteronism, RTA, Bartter/Gitelman syndrome
Transcellular shift: insulin, β2-agonists, alkalosis
Decreased intake

Clinical:

Muscle weakness, cramps, paralysis (flaccid)
Cardiac: U waves on ECG, flat T waves, arrhythmias
Hypokalemic nephropathy (polyuria)
Metabolic alkalosis

Treatment: KCl replacement; IV for severe (<2.5 or symptomatic)

Hyperkalemia (K⁺ > 5.5 mEq/L)

Causes:

Renal failure (most common)
ACE inhibitors, K-sparing diuretics (spironolactone)
Addison's disease (↓ aldosterone)
Cell lysis: rhabdomyolysis, hemolysis, tumor lysis
Acidosis (H⁺ shifts into cells, K⁺ shifts out)
Pseudohyperkalemia: prolonged tourniquet, hemolysis of sample

Clinical:

Muscle weakness
ECG changes (in order): Peaked T waves → wide QRS → sine wave → VF/asystole
Paralysis

Treatment (CBDIGK):

Calcium gluconate - membrane stabilization (immediate, 5 min)
Bicarbonate - shifts K into cells
Dextrose + Insulin - shifts K into cells (onset 20-30 min)
Inhaled β2-agonist (albuterol)
Glucose + Insulin (same as D)
K elimination: Kayexalate (sodium polystyrene) or Patiromer; Dialysis (definitive)

SECTION 4: pH REGULATION

Normal pH: 7.35-7.45

Respiratory Mechanism

CO₂ + H₂O ⇌ H₂CO₃ ⇌ H⁺ + HCO₃⁻ (carbonic anhydrase)
Lungs regulate CO₂
Acidosis: Hyperventilate → ↓ pCO₂ → ↑ pH (compensation for metabolic acidosis)
Alkalosis: Hypoventilate → ↑ pCO₂ → ↓ pH (compensation for metabolic alkalosis)
Speed: Very fast (minutes)
Henderson-Hasselbalch: pH = 6.1 + log([HCO₃⁻] / 0.03 × pCO₂)

Renal Mechanism

Three mechanisms by kidney:

Bicarbonate reabsorption (Proximal Tubule)
- H⁺ secreted into lumen via Na/H exchanger
- H⁺ + HCO₃⁻ → H₂CO₃ → CO₂ + H₂O (luminal carbonic anhydrase)
- CO₂ enters cell → HCO₃⁻ reformed → absorbed into blood
- Net effect: HCO₃⁻ is "reclaimed"
Titratable acid excretion (Distal Tubule)
- H⁺ secreted into lumen
- Combines with HPO₄²⁻ → H₂PO₄⁻ (titratable acid)
- Excreted in urine (can excrete ~30 mEq/day this way)
Ammonium excretion (Distal Tubule/Collecting Duct)
- Glutamine → NH₃ + HCO₃⁻ (regenerated bicarbonate into blood!)
- NH₃ + H⁺ → NH₄⁺ (trapped in tubular lumen → excreted)
- Most important in chronic acidosis (can increase 10-fold)
- Speed: Slow (days) but powerful

Acid-Base Disorders

Disorder	pH	Primary Change	Compensation
Metabolic Acidosis	↓	↓ HCO₃⁻	↓ pCO₂ (hyperventilate)
Metabolic Alkalosis	↑	↑ HCO₃⁻	↑ pCO₂ (hypoventilate)
Respiratory Acidosis	↓	↑ pCO₂	↑ HCO₃⁻ (kidney)
Respiratory Alkalosis	↑	↓ pCO₂	↓ HCO₃⁻ (kidney)

Compensatory Mechanisms (Winter's Formula and Rules)

Metabolic acidosis → Respiratory compensation: Expected pCO₂ = 1.5 × HCO₃⁻ + 8 (±2) (Winter's formula)
Metabolic alkalosis: Expected pCO₂ = 0.7 × HCO₃⁻ + 21 (±2)
Acute Resp. Acidosis: HCO₃⁻ ↑ by 1 for every 10 ↑ pCO₂
Chronic Resp. Acidosis: HCO₃⁻ ↑ by 3.5 for every 10 ↑ pCO₂
Acute Resp. Alkalosis: HCO₃⁻ ↓ by 2 for every 10 ↓ pCO₂
Chronic Resp. Alkalosis: HCO₃⁻ ↓ by 5 for every 10 ↓ pCO₂

Metabolic Acidosis

Causes using Anion Gap:

Anion Gap (AG)

AG = Na⁺ - (Cl⁻ + HCO₃⁻) = normally 8-12 mEq/L
Represents unmeasured anions (proteins, phosphate, sulfate)

High AG Metabolic Acidosis (MUDPILES mnemonic):

Letter	Cause
M	Methanol
U	Uremia
D	DKA
P	Propylene glycol/Paraldehyde
I	Isoniazid/Iron
L	Lactic acidosis
E	Ethylene glycol
S	Salicylates

Normal AG (Hyperchloremic) Metabolic Acidosis (DURHAM):

D - Diarrhea (loss of HCO₃⁻)
U - Ureteral diversion
R - RTA (renal tubular acidosis)
H - Hyperalimentation
A - Addison's disease
M - medications (carbonic anhydrase inhibitors)

Delta-Delta Ratio (for mixed disorders): ΔAG / ΔHCO₃⁻

<0.4: Pure non-gap metabolic acidosis
0.4-0.8: Mixed high-gap + non-gap acidosis
1-2: Pure high-gap acidosis
2: Mixed high-gap acidosis + metabolic alkalosis

Metabolic Alkalosis

Causes:

Chloride-responsive (urine Cl <20): vomiting, NG suction, loop/thiazide diuretics → Treat with NaCl
Chloride-resistant (urine Cl >20): Hyperaldosteronism (Conn's), Cushing's, Bartter, Gitelman → Treat underlying cause

Respiratory Acidosis

Causes: Hypoventilation - COPD, obesity hypoventilation, neuromuscular disease, sedation, obstructive sleep apnea
Compensation: Kidney retains HCO₃⁻

Respiratory Alkalosis

Causes: Hyperventilation - anxiety, pain, PE, early salicylate toxicity, liver failure, high altitude, pregnancy
Compensation: Kidney excretes HCO₃⁻

Mixed Acid-Base Disorders

Suspect when compensation doesn't match expected:

Examples:
- DKA + vomiting: High-AG met. acidosis + met. alkalosis
- COPD + diuretics: Resp. acidosis + met. alkalosis
- Sepsis + renal failure: Lactic acidosis + uremic acidosis
Triple disorder: Met. acidosis + met. alkalosis + resp. disorder

SECTION 5: ENZYMES

Factors Affecting Enzyme Activity

1. Substrate Concentration - Michaelis-Menten Kinetics

At low [S]: rate increases linearly (first order)
At high [S]: rate plateaus at Vmax (zero order)
Km = [S] when velocity = Vmax/2
Low Km = high affinity for substrate
Lineweaver-Burk plot (double reciprocal): x-intercept = -1/Km, y-intercept = 1/Vmax

2. Temperature

Rate doubles for every 10°C rise (Q10 = 2)
Optimal ~37°C for human enzymes
Above optimal → protein denaturation → activity ↓
Below optimal → reduced kinetic energy → activity ↓

3. pH

Each enzyme has an optimal pH
Pepsin: pH 1-2; Salivary amylase: pH 6.8; Trypsin/most enzymes: pH 7-8; Alkaline phosphatase: pH 9
Extreme pH changes denature enzyme by altering ionization of active site residues

Enzyme Regulation

Short-Term Regulation

Allosteric regulation (most important - 5 marks)
- Effectors bind to allosteric site (not active site)
- Conformational change → ↑ or ↓ activity
- Positive allosteric effectors: Activate enzyme (e.g., AMP activates PFK-1)
- Negative allosteric effectors: Inhibit enzyme (e.g., ATP, citrate inhibit PFK-1)
- Shows sigmoidal kinetics (cooperativity)
- Example: Hemoglobin (O₂ binding cooperativity), Phosphofructokinase-1
- ATCase (aspartate transcarbamoylase) - classic allosteric enzyme
- Allosteric enzymes: R state (relaxed, active) and T state (tense, inactive)
Covalent modification (3 marks)
- Phosphorylation/dephosphorylation (most common)
- Glycogen phosphorylase: phosphorylated = ACTIVE; glycogen synthase: phosphorylated = INACTIVE
- Kinases add phosphate; Phosphatases remove phosphate
- Protein kinase A (PKA) activated by cAMP
- Other covalent modifications: adenylation, methylation, acetylation
Feedback inhibition (ultra-short control)
- End product inhibits first committed enzyme of pathway
- Example: CTP inhibits ATCase (pyrimidine synthesis)

Long-Term Regulation

Enzyme Induction (Transcriptional)
- Substrate or hormone induces gene expression → more enzyme protein
- Time scale: hours to days
- Example: Cytochrome P450 induced by barbiturates, rifampicin, phenytoin, ethanol
- Example: Glucokinase induced by insulin
Enzyme Repression
- End product represses transcription of enzyme genes
- Example: Heme inhibits ALA synthase (first enzyme of heme synthesis)
- When heme accumulates → ALA synthase gene repressed

Enzyme Classification (6 major classes - IUB system)

Class	Reaction Catalyzed	Key Example
1. Oxidoreductases	Oxidation-reduction (electron transfer)	LDH, succinate dehydrogenase, catalase
2. Transferases	Transfer of functional groups	Aminotransferases (ALT, AST), kinases
3. Hydrolases	Hydrolysis	Lipase, amylase, pepsin, trypsin
4. Lyases	Addition/removal to double bonds (non-hydrolytic)	Aldolase, decarboxylases, citrate synthase
5. Isomerases	Intramolecular rearrangements	Phosphoglucose isomerase, mutases
6. Ligases (Synthetases)	Bond formation using ATP	Acetyl-CoA carboxylase, aminoacyl-tRNA synthetase

Enzyme Inhibition

Reversible Inhibition

1. Competitive Inhibition

Inhibitor structurally similar to substrate → competes for active site
Inhibitor binds active site reversibly
Vmax unchanged; Km increases
Can be overcome by ↑ substrate concentration
Lineweaver-Burk: Lines intersect on y-axis (same Vmax)
Examples: Methotrexate (DHFR), Statins (HMG-CoA reductase), Sulfonamides (PABA/DHPS)

2. Uncompetitive Inhibition

Inhibitor binds ONLY enzyme-substrate complex (ES complex)
Both Vmax and Km decrease (proportionally)
Lines on Lineweaver-Burk are parallel

3. Mixed (Non-competitive) Inhibition

Inhibitor can bind either E or ES complex (at allosteric site)
Vmax decreases; Km unchanged or changes
Pure non-competitive: Vmax ↓, Km unchanged
Example: Heavy metals (Pb, Hg) inhibiting enzymes

Irreversible Inhibition

Covalent bond formation with enzyme → permanent inactivation
Cannot be reversed by ↑ substrate
Suicide inhibitors (also called: mechanism-based inhibitors or suicide substrates or Kcat inhibitors or enzyme-activated irreversible inhibitors)
- Active substrate analogs activated by the enzyme's own active site mechanism to form covalent bond
- Examples: Aspirin (irreversibly acetylates COX), Allopurinol → oxypurinol (inhibits xanthine oxidase), Fluorouracil (inhibits thymidylate synthase), Penicillin (inhibits transpeptidase), Organophosphates (inhibit AChE)
- Other names for suicide inhibition: Mechanism-based inhibition, Kcat inhibition, suicide inactivation

Difference: Competitive vs. Non-competitive

Feature	Competitive	Non-competitive
Inhibitor binding site	Active site	Allosteric site
Effect on Vmax	No change	Decreased
Effect on Km	Increased	Unchanged (pure)
Reversible by [S]?	Yes	No
Lineweaver-Burk	Intersect on y-axis	Intersect on x-axis

Isoenzymes (Isozymes)

Multiple forms of same enzyme, same reaction, different structure (different subunits)
Encoded by different genes or different post-translational modifications

Applied aspects:

LDH (Lactate Dehydrogenase)

5 isoforms (LDH-1 to LDH-5) - made of H and M subunits (tetramers)
LDH-1 (H₄): Heart and RBCs - elevated in MI and hemolysis
LDH-5 (M₄): Liver and skeletal muscle - elevated in hepatitis
LDH-1 > LDH-2 (flip) = myocardial infarction

CK (Creatine Kinase)

CK-MM: Skeletal muscle
CK-MB: Myocardium - marker of MI (rises in 4-8h, peaks 12-24h, normalizes 48-72h)
CK-BB: Brain

Alkaline Phosphatase

Liver isoform, bone isoform, placenta isoform (Regan's enzyme)
Regan's enzyme = placental ALP isoenzyme found in some cancers (lung, ovary) - tumor marker
MCQ tip: Regan's enzyme is heat-stable (bone ALP is heat-labile; liver ALP intermediate)

Amylase

Salivary amylase (AMY1), Pancreatic amylase (AMY2)
Acute Pancreatitis: Serum amylase rises within 2-12h, peaks 12-72h, returns to normal in 3-5 days; Lipase more specific and stays elevated longer

Cardiac Markers Summary

Marker	Rises	Peaks	Normalizes	Notes
Troponin I/T	3-6h	12-24h	7-10 days	Most sensitive/specific for MI
CK-MB	4-8h	12-24h	48-72h	Used for reinfarction
Myoglobin	1-3h	6-9h	24h	First to rise, not specific
LDH-1	12-24h	48-72h	8-14 days	Historical

Cellular Markers

Enzyme/Marker	Organ	Clinical Use
ALT (GPT)	Liver (specific)	Hepatitis, liver damage
AST (GOT)	Liver, heart, muscle	Less specific
ALP	Liver, bone	Cholestasis, Paget's
GGT	Liver	Alcohol use, drug-induced
Amylase/Lipase	Pancreas	Pancreatitis
CPK-MB	Heart	MI
Troponin I/T	Heart	MI
PSA	Prostate	Prostate cancer
AFP	Liver	HCC
Acid phosphatase	Prostate	Prostate cancer (historical)
5'-Nucleotidase	Liver	Liver disease

Coenzymes and Cofactors

Cofactor: Non-protein component required for enzyme activity
- Inorganic: metal ions (Zn²⁺, Fe²⁺, Mg²⁺, Cu²⁺)
- Organic: coenzymes
Coenzyme is a type of cofactor (organic cofactor)
Coenzyme: Organic, small molecules (often vitamin-derived); loosely bound = cosubstrate; tightly bound = prosthetic group

Key Coenzymes (MCQ targets):

Coenzyme	Vitamin precursor	Function	Enzyme example
TPP (Thiamine Pyrophosphate)	Vitamin B1 (Thiamine)	Oxidative decarboxylation of α-keto acids; transketolase	Pyruvate DH, α-KG DH, BCKD, Transketolase (HMP)
FAD/FMN	Vitamin B2 (Riboflavin)	Electron/H carrier (oxidoreductase)	Succinate DH, Acyl-CoA DH
NAD⁺/NADP⁺	Vitamin B3 (Niacin)	Electron/H carrier	Most dehydrogenases; NADP in HMP, fatty acid synthesis
CoA (Coenzyme A)	Vitamin B5 (Pantothenic acid)	Acyl group transfer	Acetyl-CoA, Succinyl-CoA
PLP (Pyridoxal Phosphate)	Vitamin B6 (Pyridoxine)	Amino acid metabolism - transamination, decarboxylation, racemization, deamination	ALT, AST, amino acid decarboxylases
Biotin	Vitamin B7 (Biotin)	CO₂ transfer (carboxylation)	Pyruvate carboxylase, ACC, PCCase, MCC
THF (Tetrahydrofolate)	Vitamin B9 (Folate)	1-carbon transfer (methyl, methylene, formyl groups)	Thymidylate synthase, purine synthesis, homocysteine methylation
Cobalamin (B12)	Vitamin B12	Methyl transfer; isomerization of methylmalonyl-CoA	Methionine synthase, Methylmalonyl-CoA mutase
Lipoic acid	-	Acyl transfer (oxidative decarboxylation complex)	Pyruvate DH complex
CoQ (Ubiquinone)	-	Electron carrier in ETC	Complex I → CoQ → Complex III

Acyl-transferring coenzymes: CoA (acetyl/acyl transfer), Lipoic acid (in PDH complex)

SECTION 6: CARBOHYDRATE METABOLISM

Glucose Transporters

GLUT Transporters (Facilitated diffusion, Na-independent)

Transporter	Location	Key Features
GLUT-1	RBCs, brain, placenta	Basal glucose uptake; always expressed
GLUT-2	Liver, pancreatic β-cells, kidney, intestine	High Km (low affinity) - glucose sensor in β-cells
GLUT-3	Neurons	High affinity (low Km)
GLUT-4	Skeletal muscle, adipose tissue, heart	Insulin-stimulated (translocation from intracellular vesicles to membrane)
GLUT-5	Small intestine, testes	Fructose transporter
GLUT-12	Heart, prostate, small intestine	Insulin-regulated (like GLUT-4)

SGLT (Sodium-Glucose Cotransporters - Active transport, Na-dependent)

Transporter	Location	Function
SGLT-1	Small intestine (mainly), kidney (S3)	Absorbs glucose + galactose from gut (high affinity, low capacity); 2 Na⁺ per glucose
SGLT-2	Kidney proximal tubule (S1, S2)	Reabsorbs ~90% filtered glucose (low affinity, high capacity); 1 Na⁺ per glucose

SGLT-2 inhibitors (gliflozins - dapagliflozin, empagliflozin): Used in T2DM; block renal glucose reabsorption → glycosuria

Glycolysis

Site: Cytoplasm; occurs in all cells

Key steps:

Glucose → Glucose-6-phosphate (Hexokinase/Glucokinase - ATP used; irreversible)
G-6-P → F-6-P (Phosphoglucose isomerase)
F-6-P → F-1,6-bisphosphate (Phosphofructokinase-1/PFK-1 - ATP used; RATE-LIMITING STEP)
F-1,6-bisP → DHAP + Glyceraldehyde-3-P (Aldolase)
G-3-P → 1,3-bisphosphoglycerate (G-3-P dehydrogenase - NAD⁺ → NADH)
1,3-BPG → 3-PG (Phosphoglycerate kinase - ATP generated, substrate-level)
3-PG → 2-PG (Mutase)
2-PG → Phosphoenolpyruvate (Enolase)
PEP → Pyruvate (Pyruvate kinase - ATP generated; irreversible)

Net yield: 2 ATP, 2 NADH, 2 pyruvate per glucose

Irreversible enzymes (regulatory): Hexokinase, PFK-1, Pyruvate kinase

Allosteric regulation of PFK-1:

Activated by: AMP, ADP, F-2,6-bisphosphate (most potent activator)
Inhibited by: ATP, citrate, H⁺

Gluconeogenesis

Site: Liver (mainly), kidney cortex

4 Non-carbohydrate precursors:

Amino acids (glucogenic) - e.g., alanine (Cori/glucose-alanine cycle), glutamine
Lactate (Cori cycle: muscle → liver → glucose → muscle)
Glycerol (from triglyceride hydrolysis)
Propionate (from odd-chain fatty acid oxidation; as propionyl-CoA → succinyl-CoA → enters TCA)

Note: Even-chain fatty acids CANNOT contribute to gluconeogenesis (acetyl-CoA cannot be converted to OAA directly in mammals)

4 Key bypass enzymes (overcome irreversible glycolytic steps):

Glycolytic Enzyme (irreversible)	Gluconeogenic Bypass Enzyme
Pyruvate kinase	Pyruvate carboxylase + PEPCK
PFK-1	Fructose-1,6-bisphosphatase (FBPase-1)
Hexokinase/Glucokinase	Glucose-6-phosphatase

Pyruvate carboxylase (mitochondria): Pyruvate + CO₂ + ATP → OAA (biotin cofactor)
PEPCK (mitochondria/cytoplasm): OAA + GTP → PEP + CO₂
Fructose-1,6-bisphosphatase: F-1,6-BP → F-6-P
Glucose-6-phosphatase (ER, liver/kidney only): G-6-P → Glucose (allows glucose export)

Regulation:

Glucagon + Glucocorticoids stimulate gluconeogenesis
Insulin inhibits gluconeogenesis
PEPCK is induced by glucagon (via cAMP)

Glycogen Metabolism

Structure: α1-4 linkages in main chain; α1-6 linkages at branch points; Glycogenin is primer protein

Glycogen Synthesis:

Glucose → G-6-P (Hexokinase)
G-6-P → G-1-P (Phosphoglucomutase)
G-1-P + UTP → UDP-Glucose (UDP-glucose pyrophosphorylase - driven by PPi hydrolysis)
UDP-Glucose → Glycogen (Glycogen synthase; adds to existing chain)
Branching enzyme (α1-4 → α1-6 transglycosylase): adds branch points

Glycogenolysis:

Glycogen → G-1-P (Glycogen phosphorylase + Pi; cleaves α1-4 bonds)
Debranching enzyme: transfers 3 of 4 residues from branch to main chain; then α1-6 glucosidase releases free glucose
G-1-P → G-6-P (Phosphoglucomutase)
G-6-P → Glucose (Glucose-6-phosphatase; only liver and kidney can do this)

Regulation:

State	Glycogen Synthase	Glycogen Phosphorylase
Fed (Insulin)	Active (dephosphorylated)	Inactive
Fasted (Glucagon/Epi)	Inactive (phosphorylated)	Active (phosphorylated)

Glycogen Storage Diseases (GSDs):

Disease	Enzyme defect	Glycogen accumulated	Features
Von Gierke (Type I)	Glucose-6-phosphatase	Normal structure, liver	Hepatomegaly, hypoglycemia, hyperlipidemia, lactic acidosis
Pompe (Type II)	Lysosomal α-1,4-glucosidase (acid maltase)	All organs	Cardiomegaly, muscle weakness; only GSD with lysosomal involvement
Cori (Type III)	Debranching enzyme	Short branches, liver/muscle	Hepatomegaly, fasting hypoglycemia, myopathy
Anderson (Type IV)	Branching enzyme	Long unbranched chains	Cirrhosis
McArdle (Type V)	Muscle phosphorylase	Muscle	Muscle cramps with exercise, no rise in lactate
Hers (Type VI)	Liver phosphorylase	Liver	Mild hepatomegaly

Fructose Metabolism

Two pathways:

In muscle/adipose: Fructose + ATP → Fructose-6-phosphate (Hexokinase, low affinity)
In liver (main pathway):
- Fructose + ATP → Fructose-1-phosphate (Fructokinase, very active - bypasses PFK-1 regulation!)
- F-1-P → DHAP + Glyceraldehyde (Aldolase B)
- Glyceraldehyde → G-3-P (Triokinase)
- Then enters glycolysis/lipogenesis

Clinical:

Essential fructosuria: Fructokinase deficiency; benign; fructose in urine
Hereditary Fructose Intolerance (HFI): Aldolase B deficiency; F-1-P accumulates → inhibits glycogenolysis and gluconeogenesis → severe hypoglycemia; liver failure; AR
Dietary treatment: eliminate fructose, sucrose, sorbitol

HMP Pathway (Hexose Monophosphate / Pentose Phosphate Pathway)

Site: Cytoplasm; mainly liver, RBCs, adipose, adrenal cortex, mammary gland

Two phases:

Oxidative phase (irreversible):

G-6-P → 6-Phosphogluconolactone → 6-PG → Ribulose-5-P
Enzyme: G6PD (glucose-6-phosphate dehydrogenase) - rate-limiting
Product: 2 NADPH (reductive power) per glucose

Non-oxidative phase (reversible):

Interconversion of sugars using Transketolase (TPP cofactor) and Transaldolase
Products: Ribose-5-phosphate (for nucleotide synthesis), glycolytic intermediates

Significance of HMP pathway:

NADPH production: For fatty acid synthesis, steroid synthesis, glutathione reduction, antioxidant defense, cytochrome P450, NADPH oxidase (phagocytes)
Ribose-5-phosphate: For nucleotide/nucleic acid synthesis
Active in: RBCs (NADPH for GSH → protect against oxidative damage), liver, adrenal (steroid synthesis)
G6PD deficiency: NADPH ↓ → GSH ↓ → RBC hemolysis upon oxidative stress (primaquine, dapsone, fava beans) → hemolytic anemia; X-linked recessive; most common RBC enzyme deficiency

Polyol Pathway (Sorbitol Pathway)

Occurs in tissues with insulin-independent glucose uptake (lens, retina, peripheral nerves, kidney glomerulus, Schwann cells)
Glucose → Sorbitol (Aldose reductase; NADPH) → Fructose (Sorbitol dehydrogenase; NAD⁺)
In hyperglycemia: Excess sorbitol accumulates (can't escape cell easily)
Consequences: Osmotic damage → cataracts, peripheral neuropathy, retinopathy, nephropathy (diabetic complications)
Aldose reductase inhibitors (epalrestat): Under investigation to prevent diabetic complications

Regulation of Blood Glucose

Normal fasting: 70-100 mg/dL; 2h postprandial <140 mg/dL

Hormones:

Hormone	Effect	Mechanism
Insulin	↓ glucose (anabolic)	↑ GLUT-4 translocation; ↑ glycolysis; ↑ glycogen synthesis; ↑ lipogenesis; ↓ gluconeogenesis
Glucagon	↑ glucose (catabolic)	↑ glycogenolysis (liver); ↑ gluconeogenesis; ↓ glycolysis
Epinephrine	↑ glucose (fight/flight)	↑ glycogenolysis (liver + muscle); ↑ lipolysis
Cortisol	↑ glucose (stress)	↑ gluconeogenesis (induces PEPCK); anti-insulin
Growth hormone	↑ glucose	Anti-insulin effects

Glucose-lowering drugs: Insulin, Metformin (↑ AMPK → ↓ gluconeogenesis), Sulfonylureas (↑ insulin secretion), SGLT-2 inhibitors, GLP-1 agonists

Alcohol Metabolism

Pathway:

Ethanol → Acetaldehyde (Alcohol dehydrogenase/ADH; NAD⁺ → NADH) - mainly in cytosol
Acetaldehyde → Acetate (Aldehyde dehydrogenase/ALDH; NAD⁺ → NADH) - mitochondria
Acetate → Acetyl-CoA (in peripheral tissues)

MEOS (Microsomal Ethanol Oxidizing System): CYP2E1; induced by chronic alcohol; uses NADPH; produces ROS

Effects of High NADH/NAD⁺ ratio (acute toxicity):

↓ Gluconeogenesis → Hypoglycemia (OAA → malate; pyruvate → lactate)
↑ Lactic acid → Lactic acidosis (high AG)
↑ Lipogenesis → Fatty liver (↑ NADH → ↑ glycerol-3-P + ↑ acetyl-CoA → ↑ TAG synthesis)
↑ Ketogenesis → Alcoholic ketoacidosis
Inhibition of TCA cycle
↑ Urate production → Gout

Chronic toxicity:

Fatty liver → Alcoholic hepatitis → Cirrhosis
Wernicke-Korsakoff (thiamine deficiency)
Pancreatitis, cardiomyopathy, peripheral neuropathy

Fatty Liver (Hepatic Steatosis):

Most common alcohol-related liver disease
Mechanism: ↑ NADH → ↑ TAG synthesis; ↑ acetyl-CoA → ↑ fatty acid synthesis; ↓ fatty acid oxidation; ↓ VLDL export
Reversible with abstinence

SECTION 7: MUCOPOLYSACCHARIDES AND LYSOSOMAL STORAGE DISEASES

Mucopolysaccharides (Glycosaminoglycans - GAGs)

Definition: Unbranched polysaccharides of repeating disaccharide units (amino sugar + uronic acid)
Always negatively charged → bind cations and water → form gels
Found in ECM, mostly as proteoglycans (GAG chains covalently linked to core protein)

Types:

GAG	Sulfation	Location
Hyaluronic acid	No	Synovial fluid, vitreous, ECM
Chondroitin sulfate	Yes	Cartilage, bone, skin
Dermatan sulfate	Yes	Skin, tendons
Heparan sulfate	Yes	Basement membrane, cell surface
Keratan sulfate	Yes	Cornea, cartilage
Heparin	Yes	Mast cells (anti-coagulant)

Mucopolysaccharidoses (MPS)

Disease	Enzyme Defect	GAG accumulated	Features
Hurler syndrome (MPS I-H)	α-L-Iduronidase	Dermatan + Heparan sulfate	AR; Mental retardation, coarse facies, corneal clouding, hepatosplenomegaly, gargoylism; Autosomal RECESSIVE; NO corneal clouding in Hunter
Hunter syndrome (MPS II)	Iduronate-2-sulfatase	Dermatan + Heparan sulfate	X-linked recessive (only X-linked MPS); NO corneal clouding; mild form possible
Sanfilippo (MPS III)	Various (4 subtypes)	Heparan sulfate	Severe mental retardation, mild somatic features
Morquio (MPS IV)	Galactosamine-6-sulfatase or β-Galactosidase	Keratan sulfate	Skeletal dysplasia, normal intelligence, odontoid hypoplasia
Maroteaux-Lamy (MPS VI)	N-Acetylgalactosamine-4-sulfatase	Dermatan sulfate	Normal intelligence
Sly (MPS VII)	β-Glucuronidase	Dermatan + Heparan + Chondroitin	Variable

Key MCQ: Hurler vs Hunter: Both accumulate dermatan + heparan; Hurler is AR with corneal clouding; Hunter is X-linked without corneal clouding.

Galactosemia

AR disorder; deficiency of one of 3 enzymes:

Classic: Galactose-1-phosphate uridyl transferase (GALT) - most severe
Galactokinase deficiency (mild, cataracts only)
UDP-galactose-4-epimerase deficiency

Classic Galactosemia:

Galactose-1-phosphate accumulates → toxic to liver, brain, kidney
Presents in newborns after breast feeding or lactose-containing formula
Features: Jaundice, cataracts, hepatomegaly, E. coli sepsis, intellectual disability, renal tubular acidosis
Reducing substance in urine (positive Benedict's, Clinitest; negative glucose oxidase strip)
Treatment: Eliminate lactose and galactose from diet immediately

SECTION 8: LIPID METABOLISM

Fatty Acid Oxidation

Alpha (α) Oxidation

Site: Peroxisomes
Oxidizes fatty acids at the α-carbon (C2 position)
Used for phytanic acid (branched-chain fatty acid from diet; C3 has methyl group blocking β-oxidation)
Refsum disease: Deficiency of phytanoyl-CoA hydroxylase → phytanic acid accumulates → retinitis pigmentosa, peripheral neuropathy, cerebellar ataxia

Beta (β) Oxidation

Site: Mitochondrial matrix

Activation: Fatty acid + CoA + ATP → Acyl-CoA (Acyl-CoA synthetase; in outer mitochondrial membrane)

Entry into mitochondria:

Long-chain FA: Requires Carnitine shuttle (Carnitine acyl transferase I - rate-limiting, inhibited by malonyl-CoA)
Medium/Short chain: Directly enter

Steps (repeated for each cycle):

Acyl-CoA → Trans-Δ²-Enoyl-CoA (Acyl-CoA dehydrogenase; FAD → FADH₂)
Enoyl-CoA → L-3-Hydroxyacyl-CoA (Enoyl-CoA hydratase)
3-OH-Acyl-CoA → 3-Ketoacyl-CoA (3-Hydroxyacyl-CoA dehydrogenase; NAD⁺ → NADH)
3-Ketoacyl-CoA → Acetyl-CoA + (n-2)Acyl-CoA (Thiolase/β-ketothiolase)

ATP yield from palmitate (C16:0):

7 cycles of β-oxidation → 7 FADH₂ + 7 NADH + 8 Acetyl-CoA
8 Acetyl-CoA × 10 ATP = 80 ATP
7 FADH₂ × 1.5 ATP = 10.5 ATP
7 NADH × 2.5 ATP = 17.5 ATP
Total: 108 - 2 (activation) = 106 net ATP

Odd-chain fatty acids: Yield Propionyl-CoA in final cycle

Propionyl-CoA → Methylmalonyl-CoA (Propionyl-CoA carboxylase; biotin) → Succinyl-CoA (Methylmalonyl-CoA mutase; B12 cofactor) → TCA cycle
B12 deficiency → Methylmalonic aciduria

Unsaturated fatty acids: Need extra enzymes (isomerase, reductase); yield slightly less ATP

De Novo Synthesis of Fatty Acids

Site: Cytoplasm (liver, adipose, mammary gland)

Key enzyme: Acetyl-CoA Carboxylase (ACC) - rate-limiting enzyme

Acetyl-CoA + CO₂ + ATP → Malonyl-CoA (biotin cofactor)
Activated by: insulin, citrate
Inhibited by: glucagon, palmitoyl-CoA, AMPK

Fatty Acid Synthase (FAS) complex - multienzyme

ACP (Acyl Carrier Protein) holds intermediates
Acetyl-ACP + Malonyl-ACP → elongation by 2 carbons
Each cycle: 1 NADPH (ketoreduction) + 1 NADPH (enoyl reduction) = 2 NADPH used
Product: Palmitate (C16:0) after 7 cycles

Citrate shuttle: Acetyl-CoA from mitochondria → Citrate (crosses membrane) → Cleaved by ATP-citrate lyase in cytoplasm → Acetyl-CoA + OAA

NADPH for synthesis from: HMP pathway and Malic enzyme (malate → pyruvate + NADPH)

Triglyceride Synthesis (Triacylglycerol/TAG)

Glycerophosphate pathway (main):
1. Glycerol-3-phosphate + 2 Fatty acyl-CoA → Phosphatidic acid (PA)
2. PA + dephosphorylation → Diacylglycerol (DAG)
3. DAG + Fatty acyl-CoA → TAG (DGAT enzyme)
Occurs in: liver, adipose, intestine
Glycerol-3-phosphate source: glycolysis (DHAP) in most tissues; glycerol in liver (glycerol kinase)

Ketone Body Metabolism (Ketogenesis)

Site of synthesis: Liver mitochondria (liver CANNOT use ketone bodies!)

Steps:

2 Acetyl-CoA → Acetoacetyl-CoA (Thiolase)
Acetoacetyl-CoA + Acetyl-CoA → HMG-CoA (HMG-CoA synthase - rate-limiting)
HMG-CoA → Acetoacetate + Acetyl-CoA (HMG-CoA lyase)
Acetoacetate → β-hydroxybutyrate (β-OH-butyrate dehydrogenase; NADH)
Acetoacetate → Acetone (spontaneous decarboxylation; smell of ketones)

Ketone bodies: Acetoacetate, β-hydroxybutyrate, Acetone

Conditions favoring ketogenesis: Starvation, DKA, low-carb diet, alcoholism, prolonged exercise

Stimulated by: ↑ Acetyl-CoA, ↑ fat delivery to liver, ↓ malonyl-CoA (malonyl-CoA inhibits carnitine transferase → less FA entry → ketogenesis regulated!)

Ketolysis (Ketone Utilization)

Site: Extrahepatic tissues - brain, heart, skeletal muscle, kidney

Steps:

β-Hydroxybutyrate → Acetoacetate (β-OH-butyrate dehydrogenase; NAD⁺)
Acetoacetate + Succinyl-CoA → Acetoacetyl-CoA + Succinate (Succinyl-CoA:3-oxoacid CoA transferase / SCOT - also called thiophorase; ABSENT in liver → liver cannot use ketones)
Acetoacetyl-CoA → 2 Acetyl-CoA (Thiolase) → TCA cycle

Ketosis vs. Ketoacidosis:

Ketosis: physiological, mild ketone elevation (starvation, low-carb)
Ketoacidosis: pathological, severe (DKA, alcoholic KA); pH <7.3, high AG

Ketosis Summary (causes):

↑ FA mobilization (starvation, insulin deficiency)
↑ FA delivery to liver
↑ β-oxidation → ↑ Acetyl-CoA
OAA consumed (gluconeogenesis) → less Acetyl-CoA enters TCA
Net: ↑ Acetyl-CoA → ↑ HMG-CoA → ↑ ketone bodies

Cholesterol Metabolism

Synthesis:

Site: Liver (mainly), intestine, adrenal, gonads
Rate-limiting enzyme: HMG-CoA reductase (in ER)
HMG-CoA → Mevalonate (HMG-CoA reductase; 2 NADPH)
Mevalonate → Squalene → Lanosterol → Cholesterol
Inhibited by: statins (competitive inhibitors of HMG-CoA reductase), cholesterol itself

Regulation of HMG-CoA reductase:

Insulin: activates (dephosphorylation)
Glucagon/AMPK: inhibits (phosphorylation)
Oxysterols: decrease SREBP-2 transcription → ↓ HMG-CoA reductase

Causes of Hypercholesterolemia:

Familial hypercholesterolemia (FH): LDL receptor mutation (AR or AD) → ↑↑ LDL
Diet high in saturated fat/cholesterol
Hypothyroidism (↓ LDL receptor)
Nephrotic syndrome (↑ VLDL synthesis)
Diabetes mellitus
Drugs (steroids, thiazides)
Cholestasis
Obesity

Steroids from cholesterol:

Cholesterol → Pregnenolone (CYP11A1; side-chain cleavage) - first step
Pathways diverge to:
- Glucocorticoids (cortisol) - zona fasciculata
- Mineralocorticoids (aldosterone) - zona glomerulosa
- Sex hormones (estrogen, testosterone, progesterone) - gonads/zona reticularis
- Bile acids (primary: cholic acid, chenodeoxycholic acid) - liver
- Vitamin D (7-dehydrocholesterol → cholecalciferol in skin)

Lipoproteins (HDL, LDL, Chylomicrons)

Structure: Core (TAG, cholesterol esters) + Shell (phospholipids, free cholesterol, apoproteins)

Classification:

Lipoprotein	Source	Main Lipid	Key Apolipoproteins	Function
Chylomicrons	Small intestine	TAG (diet)	Apo B-48, Apo C-II, Apo E	Transport dietary fat from gut to tissues
VLDL	Liver	TAG (endogenous)	Apo B-100, Apo C-II, Apo E	Transport endogenous fat to tissues
IDL	From VLDL	Cholesterol+TAG	Apo B-100, Apo E	Intermediate; taken up by liver or → LDL
LDL	From IDL	Cholesterol esters	Apo B-100	Deliver cholesterol to tissues ("bad")
HDL	Liver + intestine	Protein, phospholipid	Apo A-I, Apo A-II	Reverse cholesterol transport ("good")

Chylomicron Metabolism:

Dietary fat packaged with Apo B-48 in enterocytes
Released into lymph → thoracic duct → blood
Apo C-II activates Lipoprotein Lipase (LPL) on capillary endothelium → hydrolyzes TAG → FFA released to tissues
Chylomicron remnant (depleted of TAG, retains Apo E) → taken up by liver (Apo E receptor)

LDL Metabolism:

VLDL → IDL (LPL removes TAG; Apo C-II transferred to HDL)
IDL → LDL (Hepatic lipase removes more TAG; Apo E removed; only Apo B-100 remains)
LDL → Cells via LDL receptor (Apo B-100 binds LDL receptor; receptor-mediated endocytosis)
Cholesterol ester hydrolyzed → free cholesterol → inhibits HMG-CoA reductase; activates ACAT; downregulates LDL receptor

HDL (Reverse Cholesterol Transport):

Nascent HDL (disc-shaped, Apo A-I) secreted from liver and intestine
Picks up cholesterol from peripheral tissues via ABCA1 transporter
LCAT (lecithin-cholesterol acyl transferase; activated by Apo A-I) esterifies cholesterol → core → HDL becomes spherical
Cholesterol esters transferred to VLDL/LDL via CETP (cholesteryl ester transfer protein)
HDL → liver via SR-B1 receptor (selective lipid uptake)
High HDL = protective against atherosclerosis

Eicosanoids

Derived from: 20-carbon polyunsaturated fatty acids (mainly arachidonic acid - C20:4, ω-6)
Arachidonic acid released from membrane phospholipids by Phospholipase A₂ (activated by hormones, trauma; inhibited by glucocorticoids via lipocortin)

Types:

Type	Enzyme	Key Products	Effects
Prostaglandins (PG)	COX-1, COX-2	PGE₂, PGI₂ (prostacyclin), PGF₂α	Pain, fever, inflammation; PGI₂ = vasodilator/anti-platelet
Thromboxanes (TX)	COX pathway	TXA₂	Platelet aggregation, vasoconstriction
Leukotrienes (LT)	5-Lipoxygenase	LTB₄, LTC₄, LTD₄, LTE₄ (SRS-A)	Inflammation; LTB₄ = neutrophil chemotaxis; LTC4/D4/E4 = bronchoconstriction
Lipoxins	Lipoxygenase	LXA₄	Anti-inflammatory

Aspirin:

Irreversibly acetylates COX-1 and COX-2 (serine residue in active site)
= Suicide inhibitor of COX
In platelets (no nucleus → can't make new COX) → permanent inhibition → ↓ TXA₂ → ↓ platelet aggregation
Anti-platelet effect lasts platelet lifetime (7-10 days)
Also ↓ PGI₂ but endothelial cells can regenerate COX

Phospholipids Classification

Definition: Glycerophospholipids or sphingomyelin; contain phosphate ester

Glycerophospholipids:

Backbone: Glycerol-3-phosphate
Position 1: Saturated FA; Position 2: Unsaturated FA
Position 3: Phosphate + head group

Phospholipid	Head group	Function
Phosphatidylcholine (Lecithin)	Choline	Most abundant; lung surfactant; VLDL component
Phosphatidylethanolamine (Cephalin)	Ethanolamine	Brain, clotting
Phosphatidylserine	Serine	Apoptosis signal (flips to outer leaflet)
Phosphatidylinositol	Inositol	PIP₂ → IP₃ + DAG (signaling); anchor for GPI proteins
Phosphatidylglycerol	Glycerol	Mitochondria, cardiolipin
Cardiolipin	2 phosphatidylglycerol	Inner mitochondrial membrane; antigen in syphilis (VDRL)
Plasmalogen	Vinyl ether linkage	Heart, muscle, brain
PAF (Platelet Activating Factor)	Choline, ether linkage	Platelet activation, inflammation

Sphingomyelin:

Backbone: Sphingosine (not glycerol)
Myelin sheath; stored in lysosomes
Niemann-Pick disease: Sphingomyelinase deficiency → sphingomyelin accumulation

PUFA (Polyunsaturated Fatty Acids) Significance

Essential fatty acids (EFA): Linoleic acid (C18:2, ω-6) and α-Linolenic acid (C18:3, ω-3) - cannot be synthesized in humans
ω-6 series: Linoleic → Arachidonic acid (precursor of pro-inflammatory eicosanoids)
ω-3 series: α-Linolenic → EPA (C20:5) → DHA (C22:6)
- Anti-inflammatory (EPA → anti-inflammatory eicosanoids)
- DHA: brain development, retina function
- ↓ Triglycerides, ↓ cardiovascular risk

EFA deficiency: Dermatitis (scaly skin), poor wound healing, poor growth, infertility, susceptibility to infection

SECTION 9: ELECTRON TRANSPORT CHAIN (ETC)

Site: Inner mitochondrial membrane (IMM)

Complexes:

Complex	Name	Coenzymes	Inhibitors
I	NADH: CoQ oxidoreductase	FMN, Fe-S	Rotenone, Amytal
II	Succinate: CoQ oxidoreductase	FAD, Fe-S	Carboxin, malonate (succinate dehydrogenase)
III	CoQ: Cytochrome c oxidoreductase (Cytochrome bc1)	Cyt b, Cyt c₁, Fe-S	Antimycin A
IV	Cytochrome c oxidase (Cytochrome aa₃)	Cyt a, Cyt a₃, Cu	Cyanide, CO, azide, H₂S
V	ATP synthase (F₀F₁)	-	Oligomycin (F₀), Venturicidin

Electron flow: NADH → Complex I → CoQ → Complex III → Cyt c → Complex IV → O₂

Proton pumping (Mitchell's Chemiosmotic Theory):

Complexes I, III, IV pump H⁺ from matrix to intermembrane space
Proton gradient (electrochemical gradient) drives ATP synthase (Complex V)
F₀ subunit: proton channel; F₁ subunit: ATP synthesis
P/O ratio: NADH = 2.5 ATP; FADH₂ = 1.5 ATP

Uncouplers:

Dissipate proton gradient → heat generated instead of ATP
Examples: 2,4-Dinitrophenol (DNP), Thermogenin (UCP-1) in brown adipose tissue (BAT - for thermogenesis in neonates), Carbonyl cyanide m-chlorophenylhydrazone (CCCP)
Aspirin in high doses, thyroid hormones

SECTION 10: COLLAGEN AND ECM

Collagen Structure

Most abundant protein in human body (~30% of total protein)
Triple helix of 3 α-chains; Gly-X-Y repeat sequence (Gly every 3rd position - essential!)
X and Y are often Proline and Hydroxyproline
Hydroxyproline and hydroxylysine stabilize the triple helix via H-bonds

Collagen Types (Collagen Classification)

Type	Location	Features
I	Bone, skin, tendons, dentin, cornea, sclera	Most abundant; thick fibers
II	Cartilage, vitreous humor	Thin fibers
III	Skin, blood vessels, uterus	Reticular fibers; found with type I
IV	Basement membrane	Meshwork, no fibers
V	Fetal tissue, placenta	-

Collagen Synthesis

Intracellular:

Preprocollagen mRNA → Preprocollagen (ribosome)
Signal peptide cleaved → Procollagen
Hydroxylation of Pro → Hydroxyproline (Prolyl hydroxylase; requires Vitamin C and Fe²⁺/O₂)
Hydroxylation of Lys → Hydroxylysine (Lysyl hydroxylase; requires Vit C)
Glycosylation of hydroxylysine (Gal, Glu added)
Triple helix formed (Procollagen) - C-propeptide initiates

Extracellular: 7. Procollagen secreted → N and C propeptides cleaved by Procollagen peptidase → Tropocollagen 8. Tropocollagen self-assembles into fibrils 9. Cross-linking: Lysyl oxidase (Cu²⁺-dependent) oxidizes lysine/hydroxylysine → Aldehyde → forms covalent cross-links (allysine) → mature collagen fiber

Vitamin C deficiency → Scurvy: Impaired hydroxylation → unstable collagen → bleeding gums, poor wound healing, perifollicular hemorrhage, corkscrew hairs, hemarthrosis

Copper deficiency: ↓ Lysyl oxidase → weak collagen (similar to Menkes disease - X-linked Cu deficiency)

Proteoglycans and Glycosaminoglycans

ECM Definition: The extracellular matrix (ECM) is a highly organized network of macromolecules secreted by cells into the surrounding space; provides structural support, regulates cell behavior, cell-cell communication, and tissue homeostasis.

ECM components:

Fibrous proteins: Collagen (tensile strength), Elastin (elasticity), Fibronectin (cell adhesion - RGD motif binds integrins), Laminin (basement membrane)
Proteoglycans: Core protein + GAG chains; fill space, resist compression, bind growth factors, filter molecules
Glycoproteins: Fibronectin, Laminin, Nidogen

Proteoglycans:

Core protein with covalently attached GAG chains
Examples: Aggrecan (cartilage), Decorin (skin/tendons), Perlecan (basement membrane), Syndecan (cell surface), Versican
Functions of proteoglycans/GAGs:
1. Water retention (highly hydrophilic → resist compression)
2. Structural support of ECM
3. Bind growth factors (bFGF, VEGF) and protect them from degradation
4. Cell adhesion and migration
5. Filter size and charge-based (glomerular basement membrane)
6. Anticoagulant (heparan sulfate/heparin activates AT-III)

QUICK MCQ SUMMARY TABLES

Key "First" / "Only" / "Most" Facts

Fact	Answer
Rate-limiting enzyme of glycolysis	PFK-1
Rate-limiting enzyme of gluconeogenesis	PEPCK (or Fructose-1,6-bisphosphatase)
Rate-limiting enzyme of fatty acid synthesis	Acetyl-CoA Carboxylase (ACC)
Rate-limiting enzyme of cholesterol synthesis	HMG-CoA Reductase
Rate-limiting enzyme of HMP pathway	G6PD
Rate-limiting enzyme of β-oxidation	Carnitine acyltransferase-I (CPTI)
Rate-limiting enzyme of TCA cycle	Isocitrate Dehydrogenase
Rate-limiting enzyme of urea cycle	Carbamoyl phosphate synthetase I
Enzyme deficient in Hurler syndrome	α-L-Iduronidase
Enzyme deficient in Hunter syndrome	Iduronate sulfatase
X-linked MPS	Hunter syndrome
MPS with corneal clouding	Hurler (NOT Hunter)
GSD with lysosomal involvement	Pompe disease
GSD with no rise in lactate with exercise	McArdle (Type V)
Coenzyme for oxidative decarboxylation	TPP (Thiamine pyrophosphate)
Coenzyme for carboxylation reactions	Biotin
Coenzyme for transamination	PLP (B6)
Coenzyme for 1-C transfer	THF (Folate)
Suicide inhibitor for platelets	Aspirin
Other name for suicide inhibition	Mechanism-based / Kcat inhibition
LDL receptor defect disease	Familial Hypercholesterolemia
Regan's enzyme	Placental isoform of ALP (found in lung/ovary cancer)
Tissue that cannot use ketone bodies	Liver (lacks SCOT)
GLUT-4 is stimulated by	Insulin
SGLT-2 inhibitors target	Renal proximal tubule glucose reabsorption
Color of hemosiderin on Perls stain	Blue (Prussian blue)
Mucosal block mediator	Hepcidin
Key feature: Hurler vs Hunter	Hurler = corneal clouding; Hunter = no clouding, X-linked

This covers your entire syllabus. These notes are organized for MBBS 1st year biochemistry exams with high-yield MCQ points, key enzymes, clinical correlations, and comparison tables. Study tip: focus especially on the allosteric regulation section (5 marks), enzyme inhibition comparisons (diagrams 3.27/3.29), and metabolic pathway integration.All notes are complete above. Here's a quick navigation guide to what's covered:

What's Covered - Index

Section	Topics
1. Calcium	Regulation (PTH/VitD/Calcitonin), Hypercalcemia (causes + CHIMPANZEES), Hypocalcemia, Tetany + signs
2. Iron	Absorption + pathway (DMT1/ferroportin), Mucosal block theory + Hepcidin, Iron deficiency anemia, Wilson disease, Hemosiderosis/Hemochromatosis
3. Na⁺/K⁺ Kidney	Tubular handling, Aldosterone/ADH, Hypo/hypernatremia + Pseudohypernatremia, Hypo/hyperkalemia with ECG changes + treatment
4. pH Regulation	Respiratory + Renal mechanisms, All 4 acid-base disorders, Winter's formula, Compensation rules, Anion Gap (MUDPILES), Mixed disorders, Delta-delta ratio
5. Enzymes	Michaelis-Menten, Temp/pH effects, Allosteric regulation (5m), Covalent modification, Induction (CYP450) + Repression (heme synthesis), Enzyme classification (6 classes), Competitive vs Non-competitive (comparison table), Suicide inhibition (other names), Isoenzymes - LDH/CK/ALP/Amylase, Regan's enzyme, Coenzymes table (TPP/FAD/NAD/CoA/PLP/Biotin/Folate)
6. Carbohydrates	GLUT 1-5/12, SGLT 1/2, Glycolysis (key enzymes), Gluconeogenesis (4 precursors + 4 bypass enzymes), Glycogen synthesis/lysis, Glycogen storage diseases (Type I-VI), Fructose metabolism + HFI, HMP pathway + significance + G6PD deficiency, Polyol pathway + diabetic complications, Blood glucose regulation, Alcohol metabolism + fatty liver
7. Mucopolysaccharides	GAGs classification, MPS (Hurler vs Hunter - key comparison), Galactosemia
8. Lipids	Alpha oxidation (Refsum), Beta oxidation (steps + ATP yield), Propionyl-CoA metabolism (B12), De novo synthesis (ACC/FAS), TAG synthesis, Ketogenesis (HMG-CoA), Ketolysis (SCOT), Ketosis summary, Cholesterol synthesis + steroids, Causes of hypercholesterolemia, Lipoprotein metabolism (chylomicrons/LDL/HDL), Eicosanoids + Aspirin, Phospholipid classification, PUFA significance
9. ETC	All 5 complexes + inhibitors, Chemiosmotic theory, Uncouplers
10. Collagen/ECM	Collagen types, Synthesis steps (Vit C role), Lysyl oxidase (Cu), ECM definition, Proteoglycan functions
Quick MCQ Table	All high-yield one-liners

Paper 1 *Calcium* Hypercalcemia Hypo calcemia Tetany *IRON* Mucosal block theory Anemia Wilson disease Hemosiderosis Na+ and K+regulation in kidney Hypo and hyperNatremia Hypo and hyperkalemia Pseudo hypernatremia Ph regulation by renal + respiratory mechanism Anion gap significance Calculation High AG Mixed acid base disorder Compensatory mechanism Metabolic acidosis nd alkalosis Respiratory acidosis nd alkalosis Factors affecting enzyme activity and action fig 3.18 .19 .20 Substrate concentration Tempt ph Enzyme regulations or inhibition (part of regulation) :2 types long and short term regulations Induction example:- cyt p50 by barbuttarea and repression example:- heme synthesis Long terms covalent modification 3m Allosdtresic regulation -5m imp Ultra short cm Classification of enzymes Enzyme inhibitoion reversible:- competitive Non revereselble ;- non completivve 3.27 3.29 a b Difference between competitive and nkn completivve 3.27 3.29 Other name of suicide inhibition Isoenzyme - applied aspect atleast one Acute pancreatitis, MI hepatitis Cellular markers Regans enzyme MCQ Co enzyme nd co factors Co enzyme is a part of co factors What is tpp, atp, plp , biotin , folate , co Acyl tranfering?? MCQ Enzyme classification Glycolysis Gluconeogenisis :- from 4 non carb precursor 4 key enzymes GLUT 12, 4, SGlu T 1,2 Glycogen metabolism Fructose metabolism Hmp pathway + significance Polyol pathway of glucose Regulation of blood glucose Metabolism of alcohol Glycogen disorders Acute toxicity of alcohol Fatty liver Hunter syndrome Hurler syndrome Mucopoly saccharides Galactosemia Alpha fatty oxidation Beta oxidation Metabolism of propionyl co A De novo synthesis of fat Triglycerides synthesis Ketone body metabolism Ketolysis Ketosis summary diagram Causes of HyperCholesterol Steroids synthesis from cholesterol HDL, LDL chylomicrons metabolism Eicosanoids Aspirin Classification of phospho lipid Pufa significance ETC Osmotic theory Complex inhibitors Uncouplers Collagen synthesis, structure Function of proteglycans , glyco glycans Defination of ECM

I've already written comprehensive notes for your entire Paper 1 syllabus in my previous response above. All topics are covered in full detail. Here's a quick recap of where to find each topic:

Your Paper 1 - All Topics Covered Above ✓

Your Topic	Section in Notes Above
Calcium: Hypercalcemia, Hypocalcemia, Tetany	Section 1
Iron: Mucosal block, Anemia, Wilson disease, Hemosiderosis	Section 2
Na⁺/K⁺ regulation in kidney	Section 3
Hypo/Hypernatremia, Pseudo-hypernatremia	Section 3
Hypo/Hyperkalemia	Section 3
pH regulation (Renal + Respiratory)	Section 4
Anion Gap - significance, calculation, High AG (MUDPILES)	Section 4
Mixed acid-base disorders, Compensatory mechanisms	Section 4
Metabolic/Respiratory Acidosis & Alkalosis	Section 4
Enzyme activity factors (substrate, temp, pH)	Section 5
Enzyme regulation - Induction (CYP450/barbiturates), Repression (heme)	Section 5
Long-term (Covalent modification 3m), Allosteric (5m), Feedback	Section 5
Enzyme classification (6 classes - IUB)	Section 5
Competitive vs Non-competitive inhibition (table + Lineweaver-Burk)	Section 5
Suicide inhibition - other names	Section 5
Isoenzymes: Pancreatitis, MI, Hepatitis	Section 5
Cellular markers, Regan's enzyme MCQ	Section 5
Coenzymes/Cofactors: TPP, PLP, Biotin, Folate, CoA	Section 5
Glycolysis	Section 6
Gluconeogenesis (4 precursors, 4 key enzymes)	Section 6
GLUT-4, GLUT-12, SGLT-1, SGLT-2	Section 6
Glycogen metabolism + Glycogen storage disorders	Section 6
Fructose metabolism	Section 6
HMP pathway + significance	Section 6
Polyol pathway	Section 6
Blood glucose regulation	Section 6
Alcohol metabolism, Acute toxicity, Fatty liver	Section 6
Hunter syndrome, Hurler syndrome, Mucopolysaccharides	Section 7
Galactosemia	Section 7
Alpha oxidation, Beta oxidation	Section 8
Propionyl-CoA metabolism	Section 8
De novo fat synthesis, TAG synthesis	Section 8
Ketone body metabolism, Ketolysis, Ketosis summary	Section 8
Causes of Hypercholesterolemia, Steroid synthesis	Section 8
HDL, LDL, Chylomicron metabolism	Section 8
Eicosanoids + Aspirin	Section 8
Phospholipid classification	Section 8
PUFA significance	Section 8
ETC - Chemiosmotic theory, Complex inhibitors, Uncouplers	Section 9
Collagen synthesis + structure	Section 10
Proteoglycans/GAG functions, ECM definition	Section 10

Scroll up to read the full detailed notes for each section. Everything from your syllabus is there - mechanisms, diagrams described in text, MCQ tables, clinical correlations, and comparison tables.

If you want me to expand any specific topic, add diagrams/flowcharts, create a PDF/Word document of these notes, or make practice MCQs for any section, just ask!

Vitamin B 6

Vitamin B6 (Pyridoxine) is a water-soluble B vitamin whose active form PLP (Pyridoxal Phosphate) acts as a coenzyme in amino acid metabolism - transamination, decarboxylation, and more. Deficiency causes peripheral neuropathy, dermatitis, and glossitis.

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Here are your complete, exam-ready notes on Vitamin B6:

VITAMIN B6 (PYRIDOXINE) - Complete Notes

1. Forms of Vitamin B6

Vitamin B6 is a collective term for three naturally occurring compounds, all derivatives of pyridine:

Structures of Vitamin B6 forms and Isoniazid - Lippincott Biochemistry

Form	Source	Group at C4
Pyridoxine	Plants (vegetables, grains)	-CH₂OH (hydroxymethyl)
Pyridoxal	Animal foods	-CHO (aldehyde)
Pyridoxamine	Animal foods	-CH₂NH₂ (aminomethyl)

All three are converted in the body to the active coenzyme form:

Pyridoxal Phosphate (PLP) = Active form (phosphorylated at the 5'-OH by pyridoxal kinase; requires ATP and Zn²⁺)

2. Mechanism of Action of PLP

PLP works by forming a Schiff base (aldimine) with the amino acid substrate:

PLP is covalently bound to the enzyme via a Schiff base linkage to the ε-amino group of a Lysine residue in the enzyme's active site (internal aldimine)
When an amino acid binds, it displaces lysine → external aldimine (Schiff base with amino acid substrate)
The electrons from the PLP ring act as an electron sink, stabilizing carbanion intermediates
Depending on which bond of the amino acid is broken, different reactions result:

PLP Schiff base - bonds broken determine reaction type - Basic Medical Biochemistry

Key concept: PLP is like a Swiss Army knife - the SAME coenzyme catalyzes many different reaction types depending on the enzyme and the bond broken.

3. Reactions Catalyzed by PLP

PLP is the quintessential coenzyme of amino acid metabolism - almost ALL amino acid metabolic pathways require PLP at one step.

Reaction Type	What happens	Example
Transamination	Transfer of α-amino group to α-keto acid	Alanine + α-KG ⇌ Pyruvate + Glutamate (ALT); Aspartate + α-KG ⇌ OAA + Glutamate (AST)
Deamination	Removal of amino group	Serine → Pyruvate + NH₃
Decarboxylation	Removal of COOH group	Histidine → Histamine + CO₂; DOPA → Dopamine; 5-HTP → Serotonin; Glutamate → GABA
β-Elimination	Removal of leaving group at β-carbon	Serine → Pyruvate (serine dehydratase)
γ-Elimination	Removal at γ-carbon	Cystathionine → Cysteine (cystathionase)
Racemization	L → D amino acid interconversion	Used in bacteria (cell wall synthesis)
Condensation	C-C bond formation	Glycine + Succinyl-CoA → δ-ALA (ALA synthase - first step of heme synthesis!)
Transsulfuration	Sulfur transfer	Homocysteine + Serine → Cystathionine → Cysteine (cystathionine β-synthase and cystathionase; both need PLP)

MCQ-Important PLP-dependent enzymes:

Enzyme	Reaction	Significance
ALT (GPT)	Ala + α-KG ↔ Pyruvate + Glu	Liver damage marker
AST (GOT)	Asp + α-KG ↔ OAA + Glu	Liver/heart marker
DOPA decarboxylase	DOPA → Dopamine	Parkinson's (note: carbidopa inhibits this peripherally)
Aromatic L-amino acid decarboxylase	5-HTP → Serotonin	Serotonin synthesis
Glutamate decarboxylase	Glutamate → GABA + CO₂	Inhibitory neurotransmitter synthesis (important!)
ALA synthase	Glycine + Succinyl-CoA → δ-ALA	First (rate-limiting) step of heme synthesis
Cystathionine β-synthase	Homocysteine + Serine → Cystathionine	Homocysteine metabolism
Cystathionase	Cystathionine → Cysteine	Transsulfuration pathway
Glycogen phosphorylase	Glycogen → G-1-P	Glycogenolysis (PLP acts as a structural cofactor here, NOT catalytic)
Serine hydroxymethyltransferase	Serine + THF → Glycine + CH₂-THF	1-Carbon unit donor
Kynureninase	Tryptophan pathway → NAD⁺ synthesis	B6 deficiency → ↑ xanthurenic acid excretion

4. Sources and RDA

Dietary sources: Meat, fish, poultry (rich), whole grains, vegetables, nuts, bananas, potatoes
RDA: 1.3 mg/day (adults); 1.7 mg/day (men >50); 1.5 mg/day (women >50)
Storage in body: Muscle (as PLP bound to glycogen phosphorylase - 80% of total body B6)
Absorption: Jejunum; phosphorylated forms dephosphorylated first, then absorbed, re-phosphorylated in liver

5. Deficiency of Vitamin B6

Causes:

Isoniazid (INH) therapy - most clinically important
Oral contraceptives (estrogen antagonizes B6)
Alcoholism (acetaldehyde displaces PLP from binding sites; malnutrition)
Malnutrition
Penicillamine (chelates PLP)
Cycloserine (anti-TB drug, like INH)
Hydralazine
Newborns on B6-deficient formula (historical)

Clinical Features of B6 Deficiency:

1. Neurological (most important):

Peripheral neuropathy (paresthesias, numbness, burning of hands and feet)
- Due to ↓ GABA synthesis (↓ inhibitory neurotransmitter) → hyperexcitability
- Due to ↓ myelin synthesis (B6 needed for sphingolipid synthesis)
Convulsions/Seizures (especially in infants) - due to ↓ GABA
Irritability, confusion, depression (↓ serotonin, ↓ dopamine synthesis)

2. Dermatological:

Seborrheic dermatitis (around nose, mouth, eyes)
Cheilosis (cracking at corners of mouth)
Glossitis (smooth red tongue)
Angular stomatitis

3. Hematological:

Microcytic hypochromic anemia (B6 needed for heme synthesis - ALA synthase!)
- But anemia is sideroblastic in character - iron accumulates in mitochondria of erythroblasts (ringed sideroblasts on Perls stain)
Note: This is NOT same as iron deficiency anemia; serum iron is NORMAL or HIGH

4. Metabolic:

Hyperhomocysteinemia (↓ cystathionine β-synthase and cystathionase → homocysteine accumulates → ↑ CVD risk)
Xanthurenic aciduria - diagnostic test for B6 deficiency; after tryptophan load, xanthurenic acid ↑ in urine (kynureninase needs PLP to convert kynurenine to anthranilate; without PLP, kynurenine shunted to xanthurenic acid)
Impaired niacin synthesis from tryptophan

6. Isoniazid (INH) and B6 - Exam Favorite

Mechanism of INH-induced B6 deficiency:

INH is structurally similar to PLP (both are pyridine derivatives - see structure above)
INH competes with PLP and forms an inactive hydrazone derivative with PLP (INH + PLP → INH-PLP hydrazone)
This inactivates PLP → functional vitamin B6 deficiency
Slow acetylators are more susceptible (acetylation is the main INH metabolism pathway; slow acetylators have more free INH)

Clinical result: Peripheral neuropathy (most common INH side effect)

Prevention: Give pyridoxine 25-50 mg/day with INH in at-risk patients (malnourished, alcoholics, diabetics, pregnant, HIV patients, slow acetylators)

7. Toxicity of Vitamin B6

B6 is the ONLY water-soluble vitamin with significant toxicity (all other water-soluble vitamins are relatively non-toxic in excess)

Doses >500 mg/day (nearly 400× RDA) → Sensory neuropathy
Numbness, tingling, unsteady gait, loss of proprioception
Damage is to dorsal root ganglia (sensory neurons)
Note: Motor function spared (pure sensory neuropathy)
Partial recovery on stopping supplement (not always complete)

8. Diagnostic Tests for B6 Deficiency

Tryptophan load test - Gold standard screening test
- Give oral tryptophan → measure urinary xanthurenic acid
- B6 deficient: xanthurenic acid ↑ markedly (kynureninase blocked)
Plasma PLP levels - Direct measurement (normal >30 nmol/L)
Erythrocyte AST/ALT activity - Measured before and after adding PLP in vitro
- If activity increases >25% with added PLP = deficiency

9. Special Conditions Requiring Extra B6

Condition	Reason
Homocystinuria (CBS deficiency)	High-dose B6 is TREATMENT (B6-responsive form) - saturates residual enzyme
Pyridoxine-dependent epilepsy	Rare AR disorder; seizures respond only to pharmacological doses of B6
Sideroblastic anemia	B6 may partially treat acquired (non-genetic) sideroblastic anemia
Primary hyperoxaluria type I	Pyridoxine treatment - AGT enzyme requires PLP
Pregnancy nausea/vomiting	B6 10-25 mg TDS ± doxylamine (approved first-line treatment for NVP)
Premenstrual syndrome	B6 may reduce symptoms (weak evidence)

10. Summary Table - MCQ Quick Hits

Fact	Answer
Active form of B6	Pyridoxal Phosphate (PLP)
All three dietary forms	Pyridoxine, Pyridoxal, Pyridoxamine
Main source in plants	Pyridoxine
Animal food source	Pyridoxal and Pyridoxamine
Rate-limiting enzyme of heme synthesis (needs PLP)	ALA synthase
Neurotransmitter whose synthesis needs PLP most importantly	GABA (Glutamate → GABA), also Dopamine, Serotonin
Type of anemia in B6 deficiency	Microcytic hypochromic / Sideroblastic
Drug that causes B6 deficiency	Isoniazid (INH)
Diagnostic test for B6 deficiency	Tryptophan load test → xanthurenic aciduria
Only water-soluble vitamin with toxicity	Vitamin B6
Toxicity feature	Sensory neuropathy (not motor)
Body's largest B6 store	Muscle (PLP bound to glycogen phosphorylase)
PLP bond to enzyme	Schiff base to ε-NH₂ of Lysine residue
PLP mechanism of binding substrate	External aldimine (Schiff base) formation
Two amino acids that do NOT undergo transamination	Lysine and Threonine
B6 needed for glycogen phosphorylase	Yes - but structural role, not catalytic
Condition treated with high-dose B6	Homocystinuria (B6-responsive CBS deficiency), Pyridoxine-dependent epilepsy
Drugs causing B6 deficiency besides INH	Penicillamine, Cycloserine, Hydralazine, OCP

Sources: Lippincott's Illustrated Biochemistry 8th Ed; Basic Medical Biochemistry 6th Ed; Harper's Illustrated Biochemistry 32nd Ed

Vitamin b7

Vitamin B7 (Biotin) is a water-soluble vitamin that serves as the coenzyme for all carboxylation reactions - it carries CO₂. Deficiency causes dermatitis, alopecia, and neurological symptoms, classically seen with excess raw egg white consumption (avidin binds biotin).

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Here are your complete, exam-ready notes on Vitamin B7:

VITAMIN B7 (BIOTIN) - Complete Notes

1. Basic Facts

Feature	Detail
Chemical name	Biotin (also called Vitamin H - from German Haut = skin; reflects its role in skin health)
Solubility	Water-soluble
Active form	Biotin itself (no further activation needed - unlike B1, B2, B6)
Structure	Bicyclic compound - imidazolidone ring fused with tetrahydrothiophene ring + valeric acid side chain
Binding to enzyme	Covalently bound to ε-amino group of Lysine residue in the enzyme via an amide bond
Functional group	N-1 position of biotin ring - site where CO₂ attaches

2. Structure of Biotin and Its Attachment to Enzymes

Biotin structure and attachment to lysyl residue - Lippincott Biochemistry

Biotin is covalently linked to the enzyme protein (not a cofactor that dissociates easily)
The long flexible arm (biotin + lysine = biocytin) acts like a "swinging arm" that carries CO₂ between the two active sites of the enzyme
The attachment is catalyzed by Holocarboxylase Synthetase (HCS)
Removal of biotin during enzyme turnover is catalyzed by Biotinidase

3. Function - CO₂ Carrier in Carboxylation Reactions

Biotin = CO₂ carrier coenzyme for ALL carboxylation reactions

Mechanism (2-step):

Step 1 (CO₂ fixation): Biotin + CO₂ + ATP → Carboxybiotin + ADP + Pi (CO₂ attached to N-1 of biotin ring; energy-requiring)
Step 2 (CO₂ transfer): Carboxybiotin → transfers -CO₂ to the acceptor substrate → product + free biotin regenerated

4. The 4 Biotin-Dependent Carboxylases (MCQ - ALL 4 must be memorized)

Enzyme	Reaction	Pathway	Location
1. Pyruvate Carboxylase	Pyruvate + CO₂ → Oxaloacetate	Gluconeogenesis (bypass of pyruvate kinase)	Mitochondria
2. Acetyl-CoA Carboxylase (ACC)	Acetyl-CoA + CO₂ → Malonyl-CoA	Fatty acid synthesis (rate-limiting step!)	Cytoplasm
3. Propionyl-CoA Carboxylase	Propionyl-CoA + CO₂ → Methylmalonyl-CoA	Odd-chain FA oxidation; amino acid catabolism	Mitochondria
4. β-Methylcrotonyl-CoA Carboxylase (3-MCC)	β-Methylcrotonyl-CoA → 3-Methylglutaconyl-CoA	Leucine catabolism	Mitochondria

Memory trick: "Pyruvate Acetyl Propionyl Methyl" = PAPM

Why these enzymes matter clinically:

Enzyme	Blocked in B7 deficiency → leads to
Pyruvate Carboxylase ↓	↓ Gluconeogenesis → Hypoglycemia; pyruvate accumulates → Lactic acidosis
Acetyl-CoA Carboxylase ↓	↓ Fatty acid synthesis → Abnormal lipid metabolism
Propionyl-CoA Carboxylase ↓	Propionic acid accumulation → Organic acidemia → Metabolic acidosis
3-MCC ↓	3-Methylcrotonylglycine in urine → Organic aciduria

5. Sources and Requirement

Dietary sources (in order of richness): Liver > Egg yolk (cooked) > Kidney > Milk > Peanuts > Mushrooms > Chocolate > Hazelnuts > Whole grains > Soy

Important: Biotin is also synthesized by intestinal bacteria (gut flora supply a significant amount of daily requirement)

Group	Daily Requirement
Neonates	5-6 μg/day
Children	8-12 μg/day
Adults	30 μg/day
Pregnancy	30-35 μg/day
Lactation	35 μg/day

Absorption:

Dietary protein-bound biotin is released by pancreatic biotinidase → free biotin absorbed in jejunum
Free biotin absorbed by sodium-dependent multivitamin transporter (SMVT)

6. Avidin - The Classic Story

Avidin is a glycoprotein in raw egg white that binds biotin with extremely high affinity (one of the strongest non-covalent interactions in biology)

Avidin binds 4 molecules of biotin per tetramer
Blocks biotin absorption in the intestine when raw egg whites are consumed
Heat (cooking) denatures avidin → cooked eggs do NOT cause biotin deficiency
It takes approximately 20+ raw eggs per day for a prolonged period to induce deficiency in healthy adults
Streptavidin (from Streptomyces avidinii) = bacterial analog; used extensively in laboratory techniques (ELISA, blotting, immunohistochemistry)

7. Deficiency of Vitamin B7

Causes:

Cause	Mechanism
Raw egg white consumption (dietary)	Avidin binds biotin → blocks absorption
Long-term parenteral nutrition (TPN) without biotin	No dietary biotin; no gut flora
Long-term antibiotics	Destroy biotin-producing gut bacteria
Biotinidase deficiency (genetic, AR)	Cannot recycle biotin from enzymes → functional deficiency
Holocarboxylase Synthetase deficiency (genetic, AR)	Cannot attach biotin to carboxylases → all 4 carboxylases non-functional
Anticonvulsants (valproate, carbamazepine, phenytoin)	↑ Biotin catabolism or impair liver function
Prolonged raw egg diet in infants/bodybuilders

Clinical Features of Biotin Deficiency:

Cutaneous (Skin - most visible):

Periorificial dermatitis - erythematous, scaling, crusting rash around: eyes, nose, mouth, perianal area (similar to zinc deficiency/acrodermatitis enteropathica)
Alopecia (hair loss) - can progress to total alopecia including eyebrows and eyelashes
Conjunctivitis
Glossitis (smooth, red tongue)
Angular cheilitis

Neurological:

Irritability, depression
Lethargy
Paresthesias (tingling/numbness)
Hypotonia (low muscle tone)
Seizures (especially in infants)
Ataxia (poor coordination)
Developmental delay

Metabolic (from carboxylase deficiencies):

Metabolic/lactic acidosis (pyruvate carboxylase ↓)
Organic aciduria (propionylglycine, 3-methylcrotonylglycine in urine)
Hyperammonemia (mild to moderate)
Ketoacidosis
Hypoglycemia

Immunological:

Impaired cell-mediated and humoral immunity → susceptibility to infections (Candida, bacterial)

8. Genetic Disorders of Biotin Metabolism - "Multiple Carboxylase Deficiency"

Both disorders cause deficiency of ALL 4 biotin-dependent carboxylases simultaneously:

Feature	Holocarboxylase Synthetase Deficiency	Biotinidase Deficiency
Inheritance	AR	AR
Onset	Neonatal/Early (first 6 weeks of life)	Late infantile (3 months - 2 years)
Gene	HLCS	BTD
Mechanism	Cannot attach biotin to carboxylases	Cannot recycle biotin from degraded enzymes (biotinidase cleaves biocytin → free biotin)
Metabolic	Severe metabolic/lactic acidosis, organic aciduria, hyperammonemia	Similar but milder
Neurological	Hypotonia, seizures, lethargy, developmental delay	Ataxia, seizures, hypotonia, sensorineural hearing loss (unique!), optic nerve atrophy
Skin	Periorificial dermatitis, alopecia	Periorificial dermatitis, total alopecia
Severity	More severe; can be fatal without treatment	Better outcomes with treatment
Treatment	10-40 mg/day biotin (very high dose)	5-10 mg/day biotin
Screening	Newborn screening programs	Newborn screening programs

Key MCQ: Sensorineural hearing loss that is preventable with early treatment but irreversible once present = Biotinidase deficiency

9. Biotin in Laboratory Techniques

Biotin-streptavidin system is widely used in immunoassays (ELISA, Western blot, immunohistochemistry, flow cytometry)
High-dose biotin supplements can INTERFERE with laboratory tests (including thyroid function tests, troponin, hormone assays) - a clinically important point!
Biotin-streptavidin interference: falsely high or falsely low results depending on assay design

10. Biotin Toxicity

No known toxicity of biotin even at very high doses
Upper tolerable intake limit: Not established (unlike B6)
Water-soluble → excess excreted in urine
Main concern at high doses = lab test interference (see above)

11. Summary - MCQ Quick Hits

Fact	Answer
Vitamin B7 other name	Biotin; Vitamin H
Active form	Biotin itself (no phosphorylation needed)
Function	CO₂ carrier in carboxylation reactions
Attached to enzyme via	Lysine residue (ε-amino group); amide bond
Enzyme that attaches biotin to apoenzyme	Holocarboxylase Synthetase (HCS)
Enzyme that recycles biotin from degraded enzymes	Biotinidase
Number of biotin-dependent carboxylases	4
Rate-limiting enzyme of FA synthesis (needs biotin)	Acetyl-CoA Carboxylase → makes Malonyl-CoA
First enzyme of gluconeogenesis (needs biotin)	Pyruvate Carboxylase → makes OAA
Enzyme blocked in odd-chain FA catabolism (needs biotin)	Propionyl-CoA Carboxylase
Enzyme for Leucine catabolism (needs biotin)	β-Methylcrotonyl-CoA Carboxylase
Classic cause of dietary deficiency	Raw egg white - Avidin binds biotin
Why cooked eggs are safe	Cooking denatures avidin
Early-onset multiple carboxylase deficiency	Holocarboxylase Synthetase deficiency
Late-onset multiple carboxylase deficiency	Biotinidase deficiency
Unique feature of Biotinidase deficiency	Sensorineural hearing loss
Classic skin sign of biotin deficiency	Periorificial dermatitis + Alopecia
Metabolic consequences of deficiency	Lactic acidosis, organic aciduria, hyperammonemia
Toxicity	None known (only water-soluble vitamin with NO established upper limit)
Clinical concern with high-dose biotin supplements	Interference with laboratory immunoassays
RDA (adults)	30 μg/day
Treatment: acquired deficiency	150 μg/day

Sources: Lippincott's Illustrated Biochemistry 8th Ed; Fitzpatrick's Dermatology; Basic Medical Biochemistry 6th Ed; Tietz Textbook of Laboratory Medicine

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