Nucleotide Metabolism

Clinical presentation of gout

Severe nocturnal pain in big toe

“pain resembles that of a dislocated bone…so exquisitely painful as not to endure the weight of the clothes”

Tophi

Painless urate crystal deposits that accumulate over years and can cause tissue degradation and ulcers

Hyperuricemia

High uric acid levels causing supersaturation and deposition of monosodium urate crystals

Why the big toe

Lower temperature in peripheral joints reduces urate solubility → MSU crystal formation

Clinical features of gout

Monoarticular acute arthritis, urate nephropathy, uric acid bladder stones

Nucleotide functions

DNA/RNA precursors, coenzymes, ATP/GTP energy donors, UDP/CDP carriers, allosteric regulators, second messengers

Nucleotide components

Nitrogenous base + five‑carbon sugar + ≥1 phosphate

Purine vs pyrimidine bases

Purines differ at positions 1,2,6

pyrimidines differ at positions 3,4,5

Pyrimidine biosynthesis

UMP from Gln, Asp, bicarbonate

ATP‑dependent

UMP → UTP → CTP

CPS‑II

Cytosolic carbamoyl phosphate synthetase

part of CAD multifunctional protein

UMP synthase

Multifunctional enzyme catalyzing final steps of UMP formation

Pyrimidine degradation

Ring cleavage producing ammonia, β‑alanine, malonyl‑CoA

Purine de novo synthesis

IMP from PRPP using Gly, Asp, Glu, CO₂, THF

~5 ATP required

PRPP synthetase

Generates PRPP

hereditary superactivity causes hyperuricemia

AmidoPRT

Key regulatory step of purine synthesis

activated by PRPP accumulation

AMP/GMP synthesis

Amino groups added from Asp or Gln

net neutral for glucogenic substrates

Purine salvage pathway

APRT/HGPRT attach PRPP to free bases

preferred due to lower energy cost

HGPRT deficiency

PRPP accumulation → ↑ purine synthesis → severe gout + Lesch‑Nyhan syndrome

Lesch‑Nyhan syndrome

Self‑mutilation, spasticity, intellectual disability, severe gout

SCID

Failure of B/T cell proliferation or antigen presentation

fatal without treatment

ADA deficiency

dATP accumulation inhibits ribonucleotide reductase → blocks DNA synthesis

PNP deficiency

dGTP accumulation toxic to T‑cells

AK‑2 deficiency

ATP/AMP ↔ ADP interconversion defect

immunodeficiency + deafness

SCID treatments

Pegylated ADA, bone marrow transplant, gene therapy

Uric acid excretion

~30% urine, ~60% intestinal efflux

Xanthine oxidase

Converts hypoxanthine → xanthine → uric acid

Uricase

Converts uric acid to allantoin

absent in humans

Loss of uricase

May have compensated for low blood pressure in Miocene ancestors

Uric acid danger signal

Produced during apoptosis

crystalline urate triggers immune activation

Inflammasome activation

MSU crystals activate NALP3 → IL‑1β → TNF‑α → neutrophil recruitment

Alcohol and gout

Lactic acid competes with urate

ethanol increases AMP → uric acid

ATP degradation and gout

Exercise, ethanol, fructose metabolism increase AMP → uric acid

Diet and gout

High‑protein, high‑fat, fructose, and beer worsen gout

Allopurinol

XO inhibitor used to lower uric acid

Febuxostat

Non‑purine XO inhibitor

Probenecid

Blocks renal urate reuptake transporter

Pegylated uricase

Improves uricase half‑life and reduces immunogenicity

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