Nucleotide Metabolism II

• Biosynthesis of deoxynucleotides

• Salvage Pathway• Catabolism: Purines• Catabolism:

Pyrimidines

Biosynthesis of deoxynucleotides

• Uses diphosphates (ribo) • Ribonucleotide

reducatase• 2 sub-units • R1- reduces, active and

two allosteric sites • R2- tyrosine radical

carries electrons • removes 2' OH to H

Ribonucleotide reductase reaction

• removes 2' OH to H • Thioredoxin and

NADPH

Thymidylate synthesis

• UDP ------> dUMP• dUMP --------> dTMP• required THF • methylates uracil

Regulation

THF• Mammals cannot conjugate rings or synthesize PABA.• So must get in diet.• Sulfonamides effective in bacteria due to competitive

inhibition of the incorporation of PABA

Cancer Drugs

• fluorouracil-- suicide inhibitor of Thy synthase

• aminopterin• Methotrexate --

inhibits DHF reductase

Salvage Pathway

• extra-hepatic tissues • free purines• APRT • HGPRT • Uracil• Salvage via Purine

Nucleoside phosphorylase

Lesch-Nyhan syndrome

• Lack of HGPRT • x- linked • elevates PRPP • Increase de novo

purine biosynthesis • overproduction of

urate

Catabolism: Purines

• Dietary purines: mostly degraded • Purines produce urate• excreted in urine in mammals

Degradation of uric acid

Problems

• Urate soluble 7 mg/dLat 37C

• cooler extremities, crstallizes

• synovial fluid • Gout

Treatment

• Allopurinol • inhibit xanthine oxidase• Chelates Mo 4+ • suicide inhibitor • deplete PRPP • secrete hypoxanthine/Xanthine, more soluble

Catabolism: Pyrimidines

• No problems • produce B-alanine,

NH3, and CO2

Nucleotide Catabolism: disorders

• SCID • ADA deficiency • Both B/T lymphocytes

affected • elevated dATP 50-100x • inhibit ribonucleotide

reductase • inhibit synthesis of other

deoxynucleotides• pyrimidine starvation • no cell division

Nucleotide Catabolism: disorders

• PNP deficiency • T lymphocytes • elevated dGTP• inhibit ribonucleotide

reductase • inhibit synthesis of

other deoxynucleotides

• no cell division