Nucleotide Metabolism – Vocabulary Review

A set of 38 vocabulary flashcards covering essential terms, enzymes, pathways, and drugs related to nucleotide metabolism.

Purine

Two-ring nitrogenous bases; Adenine and Guanine

Pyrimidine

A single-ring nitrogenous base. Cytosine, Uracil, Thymine

Nucleoside

Component of a nucleotide, including the nitrogenous base (purine or pyrimidine) and sugar (ribose or deoxyribose).

Nucleotide

A nucleoside with phosphate groups attaches; (1 P = nucleoside monophosphate, etc.)

Nucleobase

Adenine, Guanine, thymine, cytosine, uracil

Nucleoside

Adenosine (nucleoside + Adenine), Guanosine (Guanine), Thymidine (thymine), Cytidine (cytosine), Uridine (uracil)

De novo pathway

Route that constructs nucleotides from metabolic precursors (amino acids, CO₂, ribose-5-phosphate, NH₃)

Salvage pathway

Route that recycles free bases or nucleosides from nucleic-acid breakdown back to nucleotides

Allosteric effector

A small molecule that binds a regulatory site on an enzyme (e.g., ATP on RNR) altering catalytic activity or substrate preference.

Feedback regulation of purine synthesis

Ribose-5-P → PRPP is inhibited by allosteric regulation of PRPP kinase by ADP and GDP

IMP → Adenylosuccinate inhibited by regulation of adenylosuccinate synthetase by excess AMP without affecting GMP synthesis

PRPP → 5-phosphoribosylamine pathway partially inhibited by concerted inhibition via excess AMP and GMP

IMP → XMP inhibited by regulation of IMP DH via excess GMP, without affecting AMP synthesis

IMP biosynthesis

Ribose 5-P → (via PRPP synthetase, ATP, and Mg2+) PRPP →→ IMP; purine ring structure built one or two atoms at a time

AMP synthesis from IMP

An amino group from aspartate is added to IMP using GTP, forming Adenylosuccinate, then AMP. Fumarate is released

GMP synthesis from IMP

IMP is oxidized at C-2, generating NADH, forming XMP. Glutamine is added, forming GMP using ATP. Glutamate is released

purine catabolism

GMP → (via 5’-nuclotidase) Guanosine + Pi (leaves) → guanine + ribose (leaves) → (via hydrolytic amino group removal) xanthine (keto form)

AMP → (via 5—nucleotidase) adenosine + Pi (leaves) → (via deamination) inosine → (via hydrolyzation) hypoxanthine + ribose (leaves) → (via xanthine oxidase) xanthine

xanthine removal

xanthine → uric acid → allantoin (human stop point) → allantoate → urea → 4NH4+

Allopurinol

Inhibitor of xanthine oxidase, used for gout treatment. Allopurinol → oxypurinol, a strong competitive inhibitor to prevent uric acid build up

Pyrimidine synthesis

Pyrimidine ring synthesized as orate ring; atoms provided by aspartate + carbamoyl phosphate. This is then attached to ribose-5-P from PRPP, and converted into a pyrimidine. HCO3- + Glutamine → carbamoyl P + Aspartate → N-carbamoyl Aspartate → Dihydroorotate + PRPP → ortate → OMP → UMP → UDP → UTP → CTP

Pyrimidine catabolism

All pathways lead to NH4+ and urea synthesis. Thymine degraded to succinyl-CoA, and cytosine and uracil degraded to acetyl-CoA

DNA vs RNA

ribose = 2 OH, deoxyribose = OH, H

making deoxynucleotides

CDP → dCDP → dCTP → dUTP → dUMP → dTMP → dTDP → dTTP

UDP → dUDP → dUTP…

ribonucleotide reductase

Converts ribonucleotides to deoxyribonucleotides (CDP → dCDP, UDP → dUDP). Contains two R1 subunits, each with a substrate specificity site and a primary regulation site, with two SH groups. Has 2 R2 subunits with tyrosyl radical to strip O2 from substrates and Fe3+ cofactors

ribonucleotide reductase active site specifics

Substrate specificity site is responsive to the effector molecule that is bound:

if ATP/ dATP at substrate specificity site, UDP → dUDP + CDP → dCDP at active site (increases the affinity for pyrimidine nuleotides)

if dTTP bound, GDP → dGDP at active site (oversupply of dNTPs signaled by high levvels of dTTP)

if dGTP bound, ADP → dADP at active site

ATP at primary regulation site activates; dATP inactivates

nucleoside-diphosphate kinase (NDPK)

Catalyzes dCDP → dCTP, dUDP → dUTP; only works on diphosphate forms with a ping-pong reaction.

1. NDPK binds to a NTP1 (ATP), transferring a P group to His in the active site, forming a phosphoenzyme intermediate

2. Initially bound NDP1 (ADP) is released, bringing in a new NDP2 (any NDP/ dNDP)

3. P group transferred from NDPK-His to NDP/ dNDP, creating a new NTP/ dNTP, which is released

Thymidylate synthase (TS)

Only works on deoxy form, only monophosphates; dUMP → dTMP.

Tetrahydrofolate (folate = B9) generated from folate → dihydrofolate → tetrahydrofolate reaction, using dihydrofolate reductase.

Serine hydroxymethyltransferase converts tetrahydrofolate to N5,N10-methylene tetrahydrofolate, using a methyl from serine (leaving glycine).

dUMP → dTMP via TS by removing a methyl from N5,N10-methylene tetrahydrofolate, generating 7,8-dihydrofolate

TS inhibition

5-fluorouracil → 5-FdUMP, which acts on TS by taking methyl group instead of dTMP. Irreversible inhibition.

Aminopterin and trimethoprim compete with folate to prevent folate → dihydrofolate reaction, preventing DNA synthesis and ultimately cell division

Methotrexate, a structural analog of tetrahydrofolate, inhibits DHFR with an affinity of 100x greater than tetrahydrofolate