Chapter 25 Nucleotide Biosynthesis

Front 1

first steps of de novo synthesis of pyrimidines

Back 1

bicarbonate is phosphorylated by ATP, combines with NH3 to make carbamic acid then another ATP phosphorylates it to carbamoyl phosphate (same as first steps of urea cycle)
catalyzed by carbamoyl phosphate synthetase

Front 2

step in de novo synthesis of pyrimidines from carbamoyl phosphate to carbamoylaspartate

Back 2

catalyzed by ATCase (highly regulated)
carbamoyl phosphate is joined to aspartate

Front 3

uridylate
(and what enzyme makes it?)

Back 3

UMP
last step (sort of) of de novo synthesis of pyrimidines
reaction catalyzed by orotidyate decarboxylase

Front 4

formation of NDPs and NTPs from NMPs

Back 4

NMP + ATP-->NDP + ADP (N=any nucleotide) requires nucleotide specific enzyme (i.e. UMP kinase)
to form NTPs just need nucleoside diphosphate kinase (broad specificity)

Front 5

how is CTP formed from UTP?

Back 5

=O is replaced by NH2 from glutamine
phosphorylation followed by replacement

Front 6

ATCase

Back 6

consists of 2 catalytic trimers and 3 regulatory dimers
enzyme exists in R or T state
substrate
catalyzes reaction from carbamoyl phosphate to carbamoylaspartate (addition of aspartate)
R state stabilized by substrate
T state stabilized by CTP (product)
ATP activates ATCase to control balance

Front 7

2 differences between de novo synth of pyrimidines vs de novo synth of purines

Back 7

pyrimidines: the ring (base) is made first then attached to ribose phosphate
UTP is first product
purine: first step is to acivate ribose phosphate then components add on to make ring
IMP is first product

Front 8

de novo synthesis of purines

Back 8

first step is to activate ribose phosphate (make ring on PRPP unlike synthesis of pyrimidines)
most steps are simply phosphorylation followed by displacement

Front 9

IMP can be converted to...

Back 9

AMP and GMP--you need ATP to generate GMP, you need GTP to generate AMP (regulate each other so balanced amount)

Front 10

salvage pathway exists only for

Back 10

purines

Front 11

salvage pathway for adenine

Back 11

adenine + PRPP-->adenylate + PPi
enzyme: adenine phosphoribosyl transferase

Front 12

salvage pathway for guanine/inositine

Back 12

guanine + PRPP--> guanylate + PPi
hypoxanthine + PRPP-->inosinate + PPi
enzyme: HGPRT (hypoxanthine/guanine phosphoribosyl transferase)

Front 13

ribonucleotide reductase
(also what residues are at active site)

Back 13

catalyzes reaction for ribunucleoside diphosphate + NADPH + H+--->deoxyribonucleoside disphosphate + NADP + H2O
has 2 dimers--1 dimer has active sites made up of 3 Cys and 1 Glu
other dimer has tyroxyl-radical sites
mediated by action of free radical that moves around

Front 14

4 steps of thimidylate synthase

Back 14

1) enzyme attaches to dUMP (SH bond)
2) opens ring of methylene tetrahydrofolate
3) move methylene group
4) release thymidylate (and also dihydrofolate)

Front 15

regeneration of methylenetetrahydrofolate

Back 15

dihydrofolate is released from thimidylate synthase and dihydrofolate reductase reduces dihydrofolate to tetrahydrofolate which is then changed to methylenetetrahydrofolate

Front 16

many anticancer drugs block...

Back 16

thymidylate synthesis (cancer cells require more nucleotides because they are dividing so fast)

Front 17

mechanism for fluorodeoxyuridylate

Back 17

F-dUMP combines with methylenetetrahydrofolate which blocks thymidylate synthesis
(suicide inhibitor-enzyme won't release)

Front 18

mechanism for aminopterin and methotrexate

Back 18

analogs of dihydrofolate
competitive inhibitors of dihydrofolate reductase

Front 19

control of nucleotide biosynthesis

Back 19

purine:
1) control overall rate--formation of IMP is inhibited by IMP, AMP, and GMP
2) control balance--AMP inhibits formation of AMP, GMP inhibits formation of GMP
pyrimidine
1) ATCase regulation

Front 20

purine catabolism

Back 20

AMP-->adenosine-->inosine-->hypoxanthine-->xanthine-->uric acid-->urate-->excreted in urine
hypoxanthine and phosphoribose can be reused in salvage pathway

Front 21

xanthine oxidase

Back 21

catalyzes step from hypoxanthine to xanthine and xanthine to uric acid in purine catabolism

Front 22

nucleoside phosphorylase

Back 22

catalyzes reaction from inosine to ribose 1-P and hypoxanthine in catabolism of purines

Front 23

ADA deficiency

Back 23

genetic disease--adenosine deaminase deficiency
leads to build up of adenosine and dATP which inhibits ribonucleotide reductase and DNA synthesis
severe combined immunodeficiency
treated with gene therapy (ADA can be introduced to body)

Front 24

gout
(also how is it treated)

Back 24

excess accumulation of urate in blood (excess urate production/impaired excretion)
urate crystal accumulate in fluids and lining of joints
allopurinol reduces urate crystal accumulation by inhibiting xanthine oxidase in purine catabolism (suicide inhibtion)

Front 25

Lesch-Nyhan syndrome

Back 25

genetic disorder--near absence of HGPRT (no salvage pathway)
increased accumulation of PRPP and increased purine de novo biosynthesis
purine bases are degraded to urate
compulsive self-destructive behavior, mental deficiency and spasticity
also kidney stones due to elevated levels of urate crystals

Front 26

5 nucleotides
(5' monophosphate)

Back 26

adenylate (AMP)
guanylate (GMP)
uridylate (UMP)
cytidylate (CMP)
thymidylate (TMP)

Front 27

5 nucleosides

Back 27

adenosine
guanosine
uridine
cytidine
thymidine