Nucleotide Anabolism and Catabolism Radioisotope tracer experiments revealed

第十四章 核苷酸代谢 Nucleotide Anabolism and Catabolism

Radioisotope tracer experiments revealed the origins of the atoms in the purine and pyrimidine rings.

Purine and pyrimidine bases can be reconverted to nucleotides via the salvage pathway

Adenine or hypoxanthine-guanine phosphoribosyltransferases

⑵ IMP → → →AMP� GMP 6 6 2 2

De novo purine nucleotide synthesis: the base assembles on the ribose phosphate; IMP is first nucleotide synthesized.

The purine ring is built up one or three atoms at a time on ribose 5 -P Committing step (Unstable) 1, 3, 5 are catalyzed by one protein!

Biotin is not needed! 7 and 8 are catalyzed by one bifunctional enzyme By-product of His biosynthesis 10 and 11 are catalyzed by one bifunctional enzyme IMP is first formed before being converted to AMP and GMP.

The biosynthesis of AMP and GMP is regulated mainly by sequential feedback inhibition (no covalent regulation)

Gln amide HCO 3 The atoms of the pyrimidine rings were revealed to be derived from HCO 3 -, Gln and Asp.

All d. NDPs are derived from NDPs via the catalysis of a common ribonucleotide reductase likely via a 3`ribonucleotide radical intermediate.

Summary n n n Purine nucleotides are synthesized from PRPP, Gln, Gly, N 10 -formyl H 4 folate, HCO 3 -, Asp through the de novo pathway. Pyrimidine nucleotides are synthesized using HCO 3 -, Gln, Asp, and PRPP. De novo synthesis of nucleotides are regulated via feedback inhibition (no covalent modifications yet revealed).

n Deoxyribonucleotides are derived from ribonucleotides at the NDP level, with the catalysis of ribonucleotide reductase, which contains a chain of electron carriers, uses free radicals, and be regulated for both substrate specificity and overall enzymatic activities.

n n The d. TMP molecule is derived from d. UMP by thymidylate synthase, an enzyme using N 5, N 10 -methylene-tetrahydrofolate as the donor of both one-carbon unit and electrons. Degradation of purines and pyrimidines produces uric acid and citric acid cycle intermediate/fatty acid synthesis precursor, respectively. Purine and pyrimidine bases can be reused via the salvage pathway. Many cancer chemotherapeutic drugs (e. g. , azaserine, acivicin, fluorouracil, and methotrexate) inhibits enzymes in the nucleotide biosynthetic pathways.