purine/pyrimidine metabolism

Question 1

Drugs affecting pyrimidine synthesis

Answer 1

Leflunomide MTX, TMP, pyrimethanine 5-FU/capecitabine (prodrug)

Question 2

Drugs affecting purine synthesis

Answer 2

6-MP, azathioprine (prodrug) mycophenolate and ribavirin

Question 3

Drug that affects both pyrimidine/purine synthesis

Answer 3

Hydroxyurea inhibits ribonucleotide reductase (UDP to dUDP) build up of UDP

Question 4

inhibits dihydroorotate dehydrogenase

Answer 4

leflunomide no orotic acid (carbamoyl phosphate + aspartate) inhibit pyrimidine

Question 5

inhibits dihydrofolate reductase decrease deoxythymidine monophosphate (dTMP) in humans, bacteria, protozoa

Answer 5

MTX, TMP, pyrimethamine (inhibit pyrimidine) get build up of DHF

• MTX=eukaryotes
• TMP=prokaryotes
• pyrimethamine=protozoa

Question 6

• form 5-FdUMP
• inhibits thymidylate synthase decrease dTMP increase dUMP

Answer 6

5-FU and its prodrug capecitabine inhibit pyrimidine

Question 7

inhibit de novo purine synthesis

Answer 7

6-MP and azathioprine (prodrug) no IMP made build up of PRPP

Question 8

inhibit inosine monophosphate dehydrogenase

Answer 8

mycophenolate ribavirin build up of IMP can’t make GMP (inhibit purine)

Question 9

pyrimidine base production requires

Answer 9

aspartate

Question 10

de novo purine synthesis requires

Answer 10

aspartate glycine glutamine THF

Question 11

Start of pyrimidine synthesis

Answer 11

glutamine + CO2 + 2 ATP Carbamoyl phosphate synthetase II (CPS2) in cyTWOsol

Question 12

Start of purine synthesis

Answer 12

Ribose-5-P –> PRPP –> IMP

Question 13

In orotic acuduria, cannot make

Answer 13

UMP from orotic acid and PRPP

Question 14

one of major causes of AR SCID

Answer 14

adenosine deaminase deficiency

Question 15

adenosine deaminase is required for

Answer 15

degradation of adenosine and deoxyadenosine decrease ADA cannot make inosine from adenosine increase dATP increase lymphotoxicity = AR SCID

Question 16

Disease with defective purine salvage d/t to absent HGPRT

Answer 16

Lesch-Nyhan syndrome XR

Question 17

HGPRT converts

Answer 17

hypoxanthine to IMP guanine to GMP

Question 18

what consequences come from absent HGPRT (Lesch-Nyhan syndrome, XR)

Answer 18

excess uric acid production and de novo purine synthesis

Question 19

presentation of Lesch-Nyhan

Answer 19

XR -intellectual disability -self-mutiliation -aggression -hyperuricemia, orange “sand” [sodium rate crystals] in diaper -gout -dystonia

Question 20

How to treat Lesch-Nyhan

Answer 20

allopurinol febuxostat (2nd line) inhibit XO decrease uric acid levels

Question 21

How to Dx Lesch-Nyhan

Answer 21

increase uric acid in urine ID gene mutation

Question 22

Uric acid –> urine is done by

Answer 22

Rasburicase

Question 23

What drug increases uric acid –> urine

Answer 23

Probenicid used in gout

Question 24

What drug inhibits uric acid –> urine

Answer 24

Aspirin

Question 25

Hypoxanthine --\> Xanthine Xanthine --\> Uric acid done by

Answer 25

xanthine oxidase both inhibited by allopurinol and febuxostat

Question 26

What purine is this

Answer 26

Adenosine amino group at 12'o clock

Question 27

What purine is this

Answer 27

Guanine

Question 28

What is this molecule when 7 o' clock amino group is missing

Answer 28

hypoxanthine

Question 29

Pyrimidine with 12 o' clock amino group

Answer 29

cytosine

Question 30

pyrimidine with no 12 o ' clock amino group

Answer 30

uracil

Question 31

pyrimidine with 1 o' clock methyl group added to uracil

Answer 31

thymine

Question 32

Ribose for purine/pyrimidine synthesis made from

Answer 32

HMP shunt

Question 33

What cells have CPS2

Answer 33

cytosol of all cells EXCEPT erythrocytes

Question 34

CPS1 is located where

Answer 34

mitochondria | (urea cycle)

Question 35

carbamoyl phosphate is made in what two places

Answer 35

cytosol - de novo pyrimidine synthesis by CPS II mitochondria - urea cycle by CPS I

Question 36

what to know about orotic acid

Answer 36

it is a pyrimidine precursor

Question 37

What does thymidylate synthase do

Answer 37

adds methyl group from N5N10 methylene THF to dUMP to make dTMP

Question 38

What does dihydrofolate reductase do

Answer 38

reduces DHF and adds methyl group (from serine/glycine) to make THF

Question 39

What is a big consequence of OTC deficiency from urea cycle

Answer 39

* increase of carbamoyl phosphate in mitochondria that leaks into cytosol * carbamoyl phosphate (from mito) can be turned into pyrimidine w/CPS II * increase in orotic acid, seen in urine

Question 40

Increase of orotic acid in urine is a sign of

Answer 40

OTC deficiency from urea cycle or defective pyrimidine synthesis of orotic acid to UMP

Question 41

How to distinguish where orotic aciduria is coming from in a kid

Answer 41

* if urea cycle problem w/OTC deficiency = elevated ammonia/hyperammonemia, decreased BUN * If BUN normal, must be orotic aciduria from pyrimidine synthesis

Question 42

what is the first step of purine synthesis

Answer 42

* PRPP --\> 5-Phosphoribosylamine * via PRPP amidotransferase

Question 43

IMP can make (purine synthesis)

Answer 43

* GMP after getting amino group from glutamate * AMP after getting amino group from aspartate

Question 44

IMP, GMP, and AMP are

Answer 44

nucleotides base, (deoxy)ribose, and phosphate

Question 45

What inhibits PRPP amidotransferase

Answer 45

IMP, AMP, GMP