Lecture 26: Metabolism of Nucleotides

Question 1

NucleoSide

Answer 1

-ribose + nucleobase

Question 2

NucleoTide

Answer 2

-nucleoside + phosphate

Question 3

De novo synthesis of purine bases

Answer 3

-amino acids as carbon and nitrogen donors
-uses lots of ATP
-PRPP starting material
-first step is commitment step

Question 4

Commitment step of purine synthesis

Answer 4

-first step of PRPP to 5-phosphoribosylamine
-inhibted by AMP, GMP, IMP
-stimulated by PRPP

Question 5

IMP

Answer 5

-synthesize GMP and AMP
-this reaction inhibited by GMP and AMP

Question 6

De novo synthesis of pyrimidine bases

Answer 6

-orotate from amino acids
-OMP from orotate and PRPP
-UDP and UTP from UMP using ATP as phosphate donor
-CTP from UTP

Question 7

salvage pathway

Answer 7

-HGPRTase
-APRTase
-pyrimidine phosphoryl transferase

Question 8

HGPRTase

Answer 8

-hypoxanthine + PRPP = IMP and PPi
-guanine + PRPP = GMP + PPi

Question 9

APRTase

Answer 9

-adenine + PPRP = AMP + PPi

Question 10

NMP

Answer 10

-generated by synthesis and salvage pathways
-nucleoside monophosphate

Question 11

nucleotide kinases

Answer 11

-add phosphate groups to NMP and NDP
-ATP phosphate donor

Question 12

Degradation of purine bases

Answer 12

-purine nucleoside phosphorylase removes nucleobases
-end product is uric acid

Question 13

Uric acid

Answer 13

-not very soluble
-may form sodium urate crystals that may deposit in joints to cause gout

Question 14

Gout

Answer 14

-elevate uric acid levels
-caused by overproduction of purines, decreased excretion, alcohol and high fructose diet

Question 15

allopurinol

Answer 15

-structural isomer of hypoxanthine
-xanthine oxidase inhibitor
-reduces uric acid production
-reduces purine synthesis

Question 16

synthesis of deoxyribose nucleotides

Answer 16

-dNTP needed for DNA replication and repair
-NDP to dNDP by ribonucleotide reductase (rate-limiting)
-NADPH reducing cofactor

Question 17

ribonucleotide reducatse

Answer 17

-NDP to dNDP
-rate-limiting
-regulated by many NTPs and dNTPs

Question 18

Synthesis of Thymine

Answer 18

-dUMP to dTMP by thymidylate synthase
-THF as methyl donor

Question 19

Synthesis of NAD+

Answer 19

-vitamine
-PRPP is ribose-5-phosphate donor

Question 20

6-mercaptopurine (6-MP)

Answer 20

-antitumor frug
-converted to mononucleotide through salvage pathway
-mononucleotide inhibits PRPP-amidotransferase
-allopurinol inhibits its degradation to 6-thioruic acid by xanthine oxidase

Question 21

5-fluorouracil

Answer 21

-antitumor drug
-analog of uracil
-converted to FUMP and FdUMP
-without dTTP cells undergo tymineless death

Question 22

FUMP

Answer 22

incorporated into RNA and interferes with RNA processing

Question 23

FdUMP

Answer 23

-inhibits thymidylate synthase irreversibly via covalent bond

Question 24

Acyclovir

Answer 24

-antiviral to treat HSV
-converted to monophosphate in infected cells
-causes chain termination
-prodrug: valacyclovir is esterified version with valine = better bioavailability

Question 25

Sofobuvir (SOVALDI)

Answer 25

-antiviral for Hep C
-prodrug
-activation of nucleoside is slow
-active agent is inhibitor of NS5B which is RNA-dependent RNA polymerase