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Maple Syrup Urine Disease (MSUD)

Definition

• Incidence: ~1:185,000 to 1:200,000 live births

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Amino Acids Involved (BCAAs)

• Leucine (Leu)
• Isoleucine (Ile)
• Valine (Val)

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Metabolic Pathway (The Cycle / Steps Blocked)

BCAAs (Leucine, Isoleucine, Valine)
         |
         ↓  Step 1: TRANSAMINATION
         |  (enzyme: Branched-chain aminotransferase; coenzyme: Pyridoxal phosphate / Vit B6)
         |
    α-Keto acids (α-ketoisocaproate, α-ketomethylvalerate, α-ketoisovalerate)
         |
         ↓  Step 2: OXIDATIVE DECARBOXYLATION ← ❌ BLOCKED IN MSUD
         |  (enzyme: BCKD complex; coenzymes: TPP, Lipoic acid, FAD, NAD+, CoA)
         |
    Acyl CoA derivatives (Isovaleryl CoA, α-Methylbutyryl CoA, Isobutyryl CoA)
         |
         ↓  Step 3: DEHYDROGENATION (analogous to β-oxidation of fatty acids)
         |
    End products:
         Leucine     → Acetoacetate + Acetyl CoA   (KETOGENIC only)
         Isoleucine  → Acetyl CoA + Succinyl CoA   (BOTH ketogenic + glucogenic)
         Valine      → Succinyl CoA                (GLUCOGENIC only)

Key Enzyme Complex: BCKD

• E1α, E1β (branched-chain α-keto acid decarboxylase - uses TPP)
• E2 (dihydrolipoyl transacylase - uses Lipoic acid + CoA)
• E3 (dihydrolipoyl dehydrogenase - uses FAD + NAD+)

Important: The E3 subunit is shared with two other dehydrogenase complexes: Pyruvate dehydrogenase and α-Ketoglutarate dehydrogenase. Therefore, E3 deficiency causes a combined deficiency of all three complexes (lactic acidosis + MSUD features).

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Pathophysiology

• Accumulated leucine is primarily neurotoxic - causes cerebral edema and neurological damage
• Accumulated α-keto acids are responsible for the characteristic maple syrup odor (especially due to isoleucine metabolite)
• Results in ketoacidosis (due to ketogenic nature of leucine and isoleucine)

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Clinical Features

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Types of MSUD

1. Classic form - Most severe; no BCKD activity; neonatal onset
2. Intermediate form - Residual enzyme activity (up to 30%); milder symptoms
3. Intermittent form - Episodes triggered by high protein intake or catabolic states
4. Thiamine-responsive MSUD - Responds to pharmacological doses of Thiamine (Vit B1)
5. E3-deficient form - Combined deficiency (MSUD + lactic acidosis)

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Diagnosis

• Urine/plasma amino acid analysis: Marked elevation of leucine, isoleucine, valine + pathognomonic presence of L-alloisoleucine
• DNPH test (2,4-dinitrophenylhydrazine): Positive - characteristic precipitate (detects keto acids)
• Urine organic acids: Elevated branched-chain keto acids
• Newborn screening: Elevated leucine + isoleucine with normal phenylalanine

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Treatment

1. Diet: Synthetic formula free of all three BCAAs (Leu, Ile, Val), with controlled supplementation to allow normal growth
2. Monitor leucine closely - it is the main cause of neurological damage
3. Thiamine supplementation in responsive cases (pharmacological doses)
4. Early diagnosis is essential - delayed treatment leads to irreversible intellectual disability
5. Avoid catabolic states (illness, fasting) - catabolism of muscle protein releases BCAAs and worsens the disease

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Exam Memory Points (Vasudevan Style)

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TOPIC 1: Post-Transcriptional Modifications of mRNA

Definition

These modifications occur in the nucleus and are specific to eukaryotes.

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Overview Diagram

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Three Major Modifications

1. Addition of 5' Cap (5'-Methyl Guanosine Cap)

• Added at the 5' end of hnRNA as it is being transcribed
• A guanosine triphosphate (GTP) is added to the 5' end via an unusual 5'-to-5' triphosphate linkage
• Methyl groups are donated by S-adenosylmethionine (SAM) to position N7 of guanine
• Three cap types:
  • Cap 0: 7-methylguanosine only
  • Cap 1: Cap 0 + methyl group on 2'-OH of N1 ribose
  • Cap 2: Cap 1 + methyl group on 2'-OH of N2 ribose
• Functions:
  • Protects mRNA from 5' exonuclease degradation
  • Required for ribosome recognition/binding during translation initiation
  • Facilitates nuclear export of mRNA

Clinical link: SAM is regenerated by reactions requiring folate and Vit B12. Hence folate/B12 deficiency impairs cap synthesis.

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2. Addition of 3' Poly(A) Tail

• Added at the 3' end after transcription
• RNA polymerase reads past the stop codon until it encounters a polyadenylation signal: AAUAAA
• The primary transcript is cleaved 10-20 nucleotides downstream of this signal
• Poly(A) polymerase then adds ~200-250 adenine nucleotides to the 3' end (using ATP as substrate)
• No DNA template for the poly(A) tail - it is added post-transcriptionally
• Functions:
  • Protects mRNA from 3' exonuclease degradation
  • Helps export mRNA from nucleus
  • Facilitates translation initiation

Clinical link: A mutation AAUAAA → AACAAA in β-globin gene disrupts the polyadenylation signal, producing only 1/10th normal β-globin mRNA, causing β-thalassemia.

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3. Splicing - Removal of Introns (RNA Splicing)

• Pre-mRNA contains exons (expressed - present in mature mRNA) and introns (intervening sequences - removed)
• Consensus splice site sequences at intron boundaries are invariant:
  • 5' splice site: GU (intron begins with GU)
  • 3' splice site: AG (intron ends with AG)
  • Rule: "GU-AG rule"
• Spliceosome (large ribonucleoprotein complex) mediates splicing
  • Contains snRNPs (snurps) - small nuclear ribonucleoproteins rich in uracil: U1, U2, U4, U5, U6
  • U1 binds near 5' exon/intron junction
  • U2 binds within intron at an adenine-containing branch point
  • Intron is removed as a lariat (loop) structure

Alternative splicing: One gene can produce multiple proteins by including/excluding different exons (e.g., tropomyosin gene produces 5+ proteins).

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Summary Table

• Basic Medical Biochemistry - A Clinical Approach, 6e; Lippincott Illustrated Reviews Biochemistry, 8e

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TOPIC 2: One Carbon Metabolism

Definition

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The One-Carbon Pool Diagram

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The Carrier: Tetrahydrofolate (THF / FH4)

• Derived from dietary folate (Vitamin B9) via dihydrofolate reductase
• Carbon is carried on N5 and/or N10 positions of the pteridine ring
• FH4 exists in three interconvertible forms carrying one-carbon units at different oxidation states:

• Conversion: Formyl ↔ Methylene → Methyl (one-way; methyl form is most stable = methyl trap)

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Sources of One-Carbon Units (Donors to FH4)

FIGLU test: Histidine loading → FIGLU accumulates in urine in folate deficiency (Figlu excretion test used to diagnose folate deficiency)

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Uses of One-Carbon Units (Products)

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Role of Vitamin B12 and SAM

Homocysteine + N5-Methyl-FH4  →  Methionine + FH4
(requires Vit B12 as cofactor; enzyme: Methionine synthase)

Methionine + ATP  →  SAM (S-Adenosylmethionine)
(universal methyl donor)

SAM donates methyl group to acceptors (creatine, phosphatidylcholine,
epinephrine, melatonin, methylated DNA, methylated histones)

SAM → SAH (S-Adenosylhomocysteine) → Homocysteine (cycle restarts)

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Methyl Trap Hypothesis

• In Vitamin B12 deficiency: The enzyme methionine synthase (which uses B12) cannot function
• N5-Methyl-FH4 cannot donate its methyl group (this is the ONLY reaction that uses N5-methyl-FH4)
• Therefore, all FH4 gets "trapped" in the methyl form (most stable)
• Functional folate deficiency results despite normal total folate levels
• Cannot synthesize dTMP → cannot make DNA → Megaloblastic anemia

This explains why B12 deficiency causes megaloblastic anemia even though the direct cause is not lack of folate.

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Clinical Significance

• Basic Medical Biochemistry - A Clinical Approach, 6e; Harper's Illustrated Biochemistry, 32e; Katzung Pharmacology 16e

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TOPIC 3: DNA Repair Mechanisms

Definition

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DNA Repair Concept Map

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Types of DNA Repair

1. Mismatch Repair (MMR)

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2. Nucleotide Excision Repair (NER)

XP: Autosomal recessive disorder. Inability to repair pyrimidine dimers. Patients develop freckles, severe photosensitivity, and early skin cancers.

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3. Base Excision Repair (BER)

Note: ~10,000 purine bases are lost per cell per day by spontaneous hydrolysis (apurinic sites) - repaired by BER.

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4. Double-Strand Break (DSB) Repair

A. Non-Homologous End Joining (NHEJ)

• Proteins recognize, process, and directly ligate the broken DNA ends
• Some DNA is lost in the process
• Error-prone and mutagenic
• Occurs throughout the cell cycle (G1, S, G2)
• Defects: predisposition to cancer, immunodeficiency syndromes
• Cause of breaks: ionizing radiation, doxorubicin, free radicals

B. Homologous Recombination (HR)

• Uses enzymes from genetic recombination during meiosis
• Homologous DNA is used as template to replace lost sequences
• Error-free repair
• Occurs only in late S and G2 phases (when sister chromatid is available)
• Key proteins: BRCA1, BRCA2 (Breast Cancer 1, 2)
• Mutations in BRCA1/BRCA2 → increased risk of breast and ovarian cancer

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Comparison Summary Table

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Exam Memory Mnemonics

• "NER = UV light damage" - Nucleotide Excision Repair removes bulky UV dimers
• "BER = Bad Base Removal" - Base Excision Repair removes chemically altered individual bases
• "MMR = Mistakes Made during Replication" - corrects DNA pol errors
• BRCA = NHEJ is error-prone, HR is error-FREE using homologous template
• XP (Xeroderma Pigmentosum) = NER defect = can't fix UV damage = skin cancers
• HNPCC/Lynch syndrome = MMR defect = colon cancer
• Lippincott Illustrated Reviews Biochemistry, 8e; Basic Medical Biochemistry - A Clinical Approach, 6e; Thompson & Thompson Genetics, 9e

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TOPIC 1: Respiratory Acidosis

Definition

• ↑ PaCO2 (hypercapnia) > 45 mmHg (primary abnormality)
• ↓ pH < 7.35 (acidemia)
• Compensatory ↑ HCO3- (secondary change by kidneys)

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Henderson-Hasselbalch Basis

CO2 + H2O  ⇌  H2CO3  ⇌  H+ + HCO3-

pH = pKa + log [HCO3-] / (0.03 × PaCO2)

In respiratory acidosis:
PaCO2 ↑  →  H2CO3 ↑  →  H+ ↑  →  pH ↓

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Acid-Base Classification Diagram

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Causes of Respiratory Acidosis

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Compensation

• Renal compensation: kidneys ↑ H+ excretion (as NH4+ and titratable acid) + ↑ HCO3- reabsorption in proximal tubules
• Maximum HCO3- in compensation: ~38 mEq/L
• Respiratory compensation takes 2-5 days to fully develop

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Laboratory Values

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Clinical Features

• Rapid rise in PaCO2: Anxiety, dyspnea, confusion, psychosis, hallucinations → coma
• Chronic hypercapnia: Sleep disturbances, memory loss, daytime somnolence, personality changes, tremor, myoclonus, asterixis
• Cerebral vasodilation by CO2: Headache, papilledema, focal weakness (mimics ↑ intracranial pressure)
• Respiratory signs: Cyanosis, accessory muscle use

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Treatment

1. Treat the underlying cause (primary goal)
2. Improve ventilation: Bronchodilators (COPD), reversal agents (naloxone for opioids), non-invasive ventilation (BiPAP), mechanical ventilation if severe
3. Bicarbonate only used cautiously in mixed metabolic + respiratory acidosis (target pH > 7.20, not normalization)
4. Avoid rapid correction - sudden normalization of PaCO2 in chronic case can cause post-hypercapnic metabolic alkalosis

• Brenner & Rector's The Kidney; Sabiston Textbook of Surgery, 21e; Rosen's Emergency Medicine, 9e

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TOPIC 2: Metabolic Acidosis

Definition

• ↓ HCO3- < 22 mEq/L (primary abnormality)
• ↓ pH < 7.35 (acidemia)
• Compensatory ↓ PaCO2 (respiratory compensation via hyperventilation)

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Mechanisms (3 Ways HCO3- Falls)

1. ↑ Endogenous acid production - exceeds kidney's ability to excrete (lactic acid, ketoacids)
2. Loss of HCO3- - from GI tract (diarrhea) or kidneys (renal tubular acidosis)
3. Inability of kidneys to excrete acid - progressive accumulation of endogenous acids (CKD, RTA)

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Anion Gap (AG) - The Key Diagnostic Tool

Anion Gap = [Na+] - [Cl-] - [HCO3-]

Normal AG = 8-12 mEq/L (some sources: 3-11)

Albumin correction: For every 1 g/dL drop in albumin below 4 g/dL, add 2.5 mEq/L to calculated AG.

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Classification: High AG vs. Normal AG Metabolic Acidosis

A. High Anion Gap (HAGMA) - AG > 12 mEq/L

• Caused by accumulation of unmeasured organic/inorganic anions that consume HCO3-
• Chloride remains normal (normochloremic)

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B. Normal Anion Gap (NAGMA) / Hyperchloremic Acidosis - AG normal

• HCO3- is lost and replaced by Cl- (chloride rises proportionally)
• AG does not change

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Compensation (Respiratory Response)

Expected PaCO2 = 1.5 × [HCO3-] + 8 ± 2
   OR  ΔPaCO2 = 1.2 × ΔHCO3-

• Compensation begins within 12-24 hours
• If measured PaCO2 > expected → additional respiratory acidosis
• If measured PaCO2 < expected → additional respiratory alkalosis

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Laboratory Values

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Clinical Features

Kussmaul breathing is classically seen in DKA - fruity odor (acetone) + deep labored breathing + altered consciousness.

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Delta Gap (Delta-Delta Ratio) - Detecting Mixed Disorders

Delta Gap = (Calculated AG - Normal AG) - (Normal HCO3- - Measured HCO3-)

Delta Gap > +6  →  Concurrent Metabolic ALKALOSIS also present
Delta Gap < -6  →  Concurrent Normal AG Metabolic ACIDOSIS also present

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Treatment

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Quick Comparison Table: Respiratory vs. Metabolic Acidosis

• Brenner & Rector's The Kidney; Sabiston Textbook of Surgery 21e; Rosen's Emergency Medicine 9e

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TOPIC 1: ELISA (Enzyme-Linked Immunosorbent Assay)

Definition

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Principle

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ELISA Diagrams (Direct vs. Indirect)

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Types of ELISA

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Enzymes Used

• Horseradish Peroxidase (HRP) - most common; substrate: TMB (3,3',5,5'-tetramethylbenzidine) → blue color → yellow when stopped
• Alkaline Phosphatase (AP) - substrate: p-nitrophenyl phosphate → yellow color

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Applications

A. Tumor Markers (Cancer Diagnosis & Monitoring)

B. Immune Function / Infectious Disease

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Advantages

• High sensitivity and specificity
• Can process large batches (96-well plate format)
• Quantitative results (not just qualitative)
• No radioactive isotopes (unlike RIA)
• Relatively inexpensive and rapid

Limitations

• Cannot detect very early infection (window period for HIV)
• False positives possible (cross-reactions)
• Requires known antigen/antibody for the assay to be designed
• Indirect ELISA for HIV must be confirmed by Western blot
• Sherris & Ryan's Medical Microbiology, 8e; Tietz Textbook of Laboratory Medicine, 7e

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TOPIC 2: Xanthoma

Definition

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Pathogenesis

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Types of Xanthoma

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Lipid Disorder Association

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Clinical Significance

• Xanthelasma and corneal arcus with tendinous xanthoma in a young person = strong indicator of Familial Hypercholesterolemia (FH)
  • Homozygous FH: xanthomas in childhood; severe premature CAD
  • Heterozygous FH: xanthomas by adulthood
• Eruptive xanthomas: appear suddenly with triglycerides >1000 mg/dL; risk of pancreatitis
• Xanthoma striata palmaris: pathognomonic for Type III hyperlipidemia (dysbetalipoproteinemia / broad-beta disease)

Treatment

• Treat underlying hyperlipidemia (statins for LDL↑, fibrates/omega-3 for TG↑)
• Surgical excision for cosmetic removal of xanthelasma (but recurs if lipid disorder untreated)
• Dermatology 2-Volume Set, 5e; Henry's Clinical Diagnosis; Fitzpatrick's Dermatology

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TOPIC 3: Allopurinol

Definition

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Biochemical Background - Purine Catabolism

Adenine/Guanine (Purines)
        ↓
   Hypoxanthine / Xanthine
        ↓ ← [Xanthine Oxidase] ← BLOCKED BY ALLOPURINOL
    Uric Acid  (insoluble - deposits in joints as monosodium urate crystals → GOUT)

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Mechanism of Action

• Allopurinol is a structural analog of hypoxanthine
• It is converted by xanthine oxidase to its active metabolite alloxanthine (oxypurinol)
• Both allopurinol and alloxanthine competitively inhibit xanthine oxidase
• Result: ↓ uric acid synthesis → ↓ serum urate → ↓ urate crystal deposition in joints, kidneys, and soft tissues

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Pharmacokinetics

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Therapeutic Uses

1. Chronic gout (prevention of attacks) - first-line, preferred over febuxostat and probenecid
2. Hyperuricemia from malignancies (tumor lysis syndrome - after chemotherapy/radiation, large purine release)
3. Uric acid nephrolithiasis (kidney stones)
4. Lesch-Nyhan syndrome (HGPRT deficiency - severe hyperuricemia)
5. Heart failure (urate lowering associated with better outcomes)

Important: Allopurinol is given for prevention, NOT for acute attacks. Starting allopurinol can actually precipitate an acute gout attack due to rapid changes in serum urate.

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Adverse Effects

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Comparison with Other Urate-Lowering Agents

• Lippincott Illustrated Reviews Pharmacology; Katzung Basic & Clinical Pharmacology, 16e

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TOPIC 4: Translation - Drug Inhibition

Brief Review of Translation Steps

1. Initiation: Ribosome assembles on mRNA at start codon (AUG); initiator tRNA (Met-tRNA) enters P site
2. Elongation: Aminoacyl-tRNA enters A site → peptide bond formation (peptidyl transferase) → translocation (peptidyl-tRNA moves from A → P site, mRNA advances 3 nucleotides)
3. Termination: Stop codon (UAA, UAG, UGA) reached; release factors → polypeptide released

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Drugs That Inhibit Bacterial Translation (MBBS Key Table)

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Memory Tricks

• 30S inhibitors: Buy = Bacteriostatic aminoglycosides, Aminoglycosides (streptomycin), Tetracyclines
• 50S inhibitors: Chloramphenicol, Erythromycin (macrolides), Linezolid, Lincosamides (clindamycin)

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Key Clinical Notes

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Eukaryotic Translation - Clinically Relevant Inhibitors

• Basic Medical Biochemistry - A Clinical Approach, 6e; Medical Microbiology, 9e; Katzung Pharmacology, 16e

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TOPIC 5: Dietary Fibre

Definition

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Classification

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Digestion and Metabolism

Dietary Fiber
     ↓ (resists small intestine digestion/absorption)
     → Colon → Gut microbiota → Fermentation
     → Short-Chain Fatty Acids (SCFAs): Acetate, Propionate, Butyrate
          ↓
     SCFAs regulate:
     - Host metabolism
     - Immune system function
     - Colonic cell proliferation (butyrate is preferred fuel for colonocytes)

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Health Benefits

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Recommended Intake (AI - Adequate Intake)

• Women: 25 g/day
• Men: 38 g/day
• Average American diet: only ~15 g/day (deficient)

Note: Fiber should be introduced gradually to the diet - sudden increase causes abdominal discomfort, gas, bloating, and diarrhea.

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Glycemic Index and Fiber

• Glycemic Index (GI) ranks carbohydrate foods based on blood glucose response
• Fiber blunts the glycemic response by slowing gastric emptying and absorption
• Low GI (<55) foods are typically high in fiber
• Low-GI diets improve glycemic control in diabetics

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Functional Fiber

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Sources of Fiber

• Lippincott Illustrated Reviews Biochemistry, 8e

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TOPIC 6: Cell Cycle Stages

Definition

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Cell Cycle Diagram

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Phases of the Cell Cycle

INTERPHASE (90% of total cycle time)

1. G1 Phase (Gap 1 / First Growth Phase)

• Period before DNA synthesis
• Cell grows in size; organelles duplicated
• Protein and RNA synthesis ↑
• Metabolically active: producing materials for DNA replication
• DNA content: 2N (diploid)
• Key checkpoint: G1/S checkpoint (Restriction point) - decides whether cell will divide
• Cells that stop dividing exit to G0 from G1

2. S Phase (Synthesis Phase)

• DNA replication occurs
• Each chromosome is replicated to form 2 sister chromatids
• DNA content doubles: 2N → 4N
• Histone synthesis also occurs (for packaging new DNA)
• Duration: ~6-8 hours

3. G2 Phase (Gap 2 / Second Growth Phase)

• Period after DNA synthesis, before mitosis
• Cell checks DNA was replicated correctly
• Proteins for mitosis (e.g., tubulin for spindle) are synthesized
• DNA content: 4N (tetraploid)
• Key checkpoint: G2/M checkpoint - ensures DNA is intact before division

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M PHASE (Mitosis) - ~1 hour

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G0 Phase (Quiescence)

• Cells that have exited the cell cycle
• Non-dividing, resting state (reversible)
• Examples: mature T lymphocytes, neurons, hepatocytes (can be stimulated back)
• Permanently non-dividing cells (terminally differentiated): neurons, cardiac muscle cells, skeletal muscle cells

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Cell Cycle Checkpoints

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Regulators of the Cell Cycle

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DNA Content Through the Cell Cycle

G1:  2N (diploid)
S:   2N → 4N (synthesis in progress)
G2:  4N (tetraploid)
M:   4N → 2N + 2N (each daughter cell diploid)

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Clinical Relevance: Cell Cycle and Cancer Drugs

• Lippincott Illustrated Reviews Biochemistry, 8e; Basic Medical Biochemistry - A Clinical Approach, 6e; Quick Compendium of Clinical Pathology, 5e

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MBBS Biochemistry - Master Summary Sheet

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1. Maple Syrup Urine Disease (MSUD)

• Defect: BCKD complex (Branched-chain α-keto acid dehydrogenase)
• Inheritance: Autosomal recessive
• Affected AAs: Leucine, Isoleucine, Valine (BCAAs)
• Urine odor: Maple syrup (due to isoleucine metabolite)
• Neurotoxic: Leucine (cerebral edema)
• BCKD cofactors: TPP, Lipoic acid, FAD, NAD+, CoA
• E3 subunit shared with PDH and α-KGDH complexes
• Leucine end products: Acetoacetate + Acetyl CoA (purely ketogenic)
• Valine: Succinyl CoA (glucogenic); Isoleucine: Both
• Dx: Plasma AA analysis, DNPH test positive, L-alloisoleucine pathognomonic
• Tx: BCAA-free synthetic diet; thiamine in responsive variants

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2. Post-Transcriptional Modifications (mRNA Processing)

• β-thalassemia clinical link: AAUAAA → AACAAA mutation destroys polyadenylation signal
• SAM for cap synthesis requires Folate + Vit B12 for regeneration

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3. One Carbon Metabolism

• Carrier: Tetrahydrofolate (FH4) derived from Folate (Vit B9)
• Carbon carried on: N5 and/or N10 positions
• Three forms: N10-Formyl (most oxidized) ↔ N5,N10-Methylene ↔ N5-Methyl (most reduced/stable)
• Sources: Serine (major), Glycine, Histidine, Formate, Formaldehyde
• Products: dTMP (methylene-FH4), Purine C2 & C8 (formyl-FH4), Methionine (methyl-FH4 + B12)
• SAM (S-adenosylmethionine): universal methyl donor → creatine, phosphatidylcholine, epinephrine, DNA methylation
• Methyl Trap: B12 deficiency → N5-methyl-FH4 accumulates → functional folate deficiency → megaloblastic anemia
• FIGLU test: Histidine loading → FIGLU in urine = folate deficiency

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4. DNA Repair Mechanisms

• BER steps: Glycosylase removes base → AP endonuclease cuts → lyase removes sugar → DNA pol I fills gap → ligase seals
• NHEJ = error prone; HR = error free (uses homologous template, occurs in S/G2)

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5. Respiratory Acidosis

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6. Metabolic Acidosis

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7. ELISA

• Enzymes: HRP (TMB substrate → blue), Alkaline Phosphatase (p-nitrophenyl phosphate → yellow)
• HIV ELISA: indirect; must confirm with Western blot
• Tumor markers: AFP (HCC), PSA (prostate), CEA (colorectal), CA-125 (ovarian), β-hCG (choriocarcinoma)

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8. Xanthoma

• Pathogenesis: Hyperlipidemia → macrophage foam cells in skin/tendons
• Treatment: Statin (↑LDL), Fibrate (↑TG)

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9. Allopurinol

• Class: Xanthine oxidase inhibitor (purine analog, structural analog of hypoxanthine)
• Mechanism: Blocks last 2 steps of uric acid synthesis; converted to active metabolite alloxanthine (oxypurinol)
• Used for: Chronic gout prevention, tumor lysis syndrome, uric acid kidney stones
• Dosing: Once daily (alloxanthine t½ = 15-18 hrs); renally cleared - dose reduce if eGFR <30
• Key ADR: Skin rash/hypersensitivity (most common); starts gout flare (add colchicine for 6 months)
• Critical drug interaction: Inhibits xanthine oxidase → cannot metabolize azathioprine / 6-MP → dose reduce by 75% to avoid bone marrow suppression
• Compare: Febuxostat (non-purine XO inhibitor); Probenecid (uricosuric); Colchicine (anti-inflammatory, not urate-lowering)

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10. Translation - Drug Inhibition

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11. Dietary Fibre

• Recommended intake: 25 g/day (women), 38 g/day (men); average ~15 g/day
• Absorbs 10-15× its weight in water → bulk → laxation
• Butyrate = preferred fuel for colonocytes; promotes apoptosis of colon cancer cells
• Introduce gradually - sudden increase → gas, bloating

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12. Cell Cycle Stages

G0 ← Exit ←─── G1 ──→ S ──→ G2 ──→ M ──→ (repeat)
(quiescence)  (2N)   (2N→4N)  (4N)   (4N→2N+2N)

• G1/S (Restriction point): Cyclin D + CDK4/6; Rb; p53 → mutated in most cancers
• G2/M: Cyclin B + CDK1 (MPF)
• Spindle: APC/C complex

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Exam tip: These 12 topics cover amino acid disorders, molecular biology (transcription/translation/DNA repair), acid-base physiology, lipid disorders, pharmacology, and nutrition - all high-yield areas for MBBS Biochemistry theory and MCQs.