Explain the metabolism of nucleotides in simplest way with flowchart

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Nucleotide Metabolism - Simplified

What is a Nucleotide?

A nucleotide = Base + Sugar + Phosphate(s)

Component	Options
Base	Purine (A, G) or Pyrimidine (C, T, U)
Sugar	Ribose (RNA) or Deoxyribose (DNA)
Phosphate	1, 2, or 3 groups

The Big Picture - Nucleotide Metabolism Has 3 Parts

NUCLEOTIDE METABOLISM
        │
   ┌────┴─────┐
   │          │
PURINES   PYRIMIDINES
(A, G)    (C, T, U)
   │          │
   └────┬─────┘
        │
   Each has 3 fates:
   ┌────┴──────┬──────────┐
   │           │          │
DE NOVO     SALVAGE  DEGRADATION
SYNTHESIS   PATHWAY   (breakdown)
(build       (recycle   (waste
 from        old bases)  products)
 scratch)

PART 1 - PURINE METABOLISM

Purine Bases: Adenine (A) and Guanine (G)

A. De Novo Synthesis (Building from Scratch)

Ribose-5-phosphate (from pentose phosphate pathway)
           │
           ▼  (activated by PRPP synthetase)
          PRPP
(5-phosphoribosyl-1-pyrophosphate)
           │
           ▼  ← Glutamine donates N
           │    [REGULATED STEP - enzyme: GPAT]
           │    inhibited by AMP & GMP (end-products)
           ▼
  5-Phosphoribosylamine
           │
           ▼  (10 more enzymatic steps
           │   atoms come from: Glycine, Glutamine,
           │   CO₂, Aspartate, Folate/THF)
           ▼
          IMP  ← (Inosine Monophosphate = branch point)
        ┌──┴──┐
        ▼     ▼
       AMP   GMP
        │     │
        ▼     ▼
       ADP   GDP
        │     │
        ▼     ▼
       ATP   GTP    ← Used in RNA synthesis

B. Salvage Pathway (Recycling Old Bases)

Free purine bases (from cell turnover / diet)
        │
        ▼  + PRPP
  HGPRT enzyme  → Hypoxanthine → IMP → AMP/GMP
  APRT enzyme   → Adenine → AMP

[HGPRT deficiency = Lesch-Nyhan Syndrome]
(self-mutilation, hyperuricemia, gout)

C. Purine Degradation

AMP → Adenosine → Inosine → Hypoxanthine
GMP → Guanosine → Guanine → Xanthine
                              │
                              ▼  (xanthine oxidase - XO)
                           XANTHINE
                              │
                              ▼  (xanthine oxidase - XO)
                           URIC ACID
                         (final waste product)
                              │
                    ┌─────────┴─────────┐
                    ▼                   ▼
              Excreted in urine    ↑ Uric acid = GOUT
              (normal)            (MSU crystal deposits)

[Allopurinol inhibits XO → treats gout]

PART 2 - PYRIMIDINE METABOLISM

Pyrimidine Bases: Cytosine (C), Uracil (U), Thymine (T)

A. De Novo Synthesis

Key difference from purines: the ring is built BEFORE being attached to ribose

CO₂ + Glutamine + ATP
           │
           ▼  [REGULATED STEP - enzyme: CPS II]
           │  Inhibited by UTP (end-product)
           │  Activated by PRPP
           ▼
    Carbamoyl Phosphate
           │
           ▼  + Aspartate
    Carbamoyl Aspartate
           │
           ▼
    Dihydroorotate
           │
           ▼
         Orotate
           │
           ▼  + PRPP  (now attached to ribose)
          OMP  (Orotidine 5'-monophosphate)
           │
           ▼
          UMP  (Uridine monophosphate)
           │
     ┌─────┴──────┐
     ▼             ▼
    UTP           dUMP
     │              │  (thymidylate synthase + folate/THF)
     ▼              ▼
    CTP            dTMP  ← needed for DNA only

Note: UMP synthase deficiency = Orotic Aciduria (orotic acid builds up in urine)

PART 3 - DEOXYRIBONUCLEOTIDE SYNTHESIS

All deoxyribonucleotides (for DNA) come from reducing ribonucleotides:

Ribonucleoside diphosphates (ADP, GDP, CDP, UDP)
               │
               ▼  [Ribonucleotide reductase - RNR]
               │  NADPH provides reducing power (via Thioredoxin)
               │  Strongly inhibited by dATP
               ▼
Deoxyribonucleoside diphosphates (dADP, dGDP, dCDP, dUDP)
               │
               ▼
         Used in DNA synthesis

[Hydroxyurea inhibits RNR → anticancer drug]

Master Overview Flowchart

DIETARY NUCLEOTIDES (mostly degraded in GI tract)
             │
             ▼
    ┌────────────────────────────────────┐
    │        CELL MAKES NUCLEOTIDES       │
    │  via 2 routes:                      │
    │   1. DE NOVO (from amino acids,    │
    │      CO₂, folate, ribose-5-P)      │
    │   2. SALVAGE (recycle old bases)   │
    └────────────────────────────────────┘
             │
     ┌───────┴────────┐
     ▼                ▼
  PURINES         PYRIMIDINES
 (IMP → AMP/GMP) (OMP → UMP → UTP/CTP)
     │                │
     └───────┬─────────┘
             ▼
    RIBONUCLEOTIDES (NTPs)
     → Used in RNA synthesis
     → Used as energy (ATP)
     → Signal molecules (cAMP, cGMP)
             │
             ▼  [Ribonucleotide reductase]
    DEOXYRIBONUCLEOTIDES (dNTPs)
     → Used in DNA synthesis
             │
     ┌───────┴────────┐
     ▼                ▼
  PURINES          PYRIMIDINES
  degraded to      degraded to
  URIC ACID        CO₂ + NH₃
  (excreted)       (easily cleared)

Key Concept Map (from Lippincott's Biochemistry)

Quick Summary Table

Feature	Purines (A, G)	Pyrimidines (C, U, T)
Ring built	On ribose (PRPP first)	Off ribose, then attached
Regulated step	GPAT (inhibited by AMP, GMP)	CPS II (inhibited by UTP)
Activated by	PRPP	PRPP
Salvage enzyme	HGPRT / APRT	Not prominent
Degradation product	Uric acid	CO₂ + NH₃
Key disease	Gout, Lesch-Nyhan	Orotic aciduria

Key Drugs That Target Nucleotide Metabolism

Drug	Target	Use
Allopurinol	Xanthine oxidase	Gout
Hydroxyurea	Ribonucleotide reductase	Cancer, sickle cell
Methotrexate	Dihydrofolate reductase (blocks THF for TMP synthesis)	Cancer, autoimmune
5-Fluorouracil	Thymidylate synthase (blocks dTMP)	Cancer
Sulfonamides	Folate synthesis in bacteria	Antibacterial

Source: Biochemistry, 8th ed. Lippincott Illustrated Reviews, Chapter 22

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