Nucleotide Metabolism

Front 1

what enzyme synthesizes PRPP? and from what?

Back 1

the enzyme is PRPP synthetase

the reaction is:
Ribose-5-phosphate +ATP -> PRPP + AMP

Front 2

what is the first reaction that makes IMP? what is the enzyme?

Back 2

it is

PRPP + Glutamine - > 5-Phosphoribosylamine + glutamate +PPi

the enzyme is Glutamine PRPP amidotransferase aka amido phosphoribosyltransferase

Front 3

what is needed to convert IMP to AMP? what is needed to convert IMP to GMP?

Back 3

IMP to AMP you need GTP

IMP to GMP you need ATP

both AMP and GMP inhibit their own synthesis which helps keep the proper A to G ratio

Front 4

what is the pathway for the degration of AMP?

Back 4

yeah look it up if you dont know it by now.

Front 5

what 2 enzymes are used for the purine salvage reaction?

Back 5

HPRT (HGPRT)

Hypoxanthine + PRPP -> IMP + PPi
Guanione + PRPP -> GMP + PPi

APRT
Adenine + PRPP -> AMP to PPi

Front 6

what is the first reaction in the pyrimidine synthesis?
What is the enzyme and where is it found?

Back 6

CO2 + Glutamine + 2ATP -> Carbamoylphosphate + 2 ADP +Pi + Glutamate

the enzyme is Carbamoylpphosphate Synthetase II; found in the cytosol

Front 7

what is the 2nd reaction in pyrimidine synthesis?
what is the enzyme and where is it found?

Back 7

Carbamoylphosphate + Aspartate -> Carbamoylaspartate + Pi

enzyme -> aspartate transcarbamoylase found in the cytosole

Front 8

what is the 3rd reaction in pyrimidine synthesis?
what is the enzyme and where is it found?

Back 8

Carbamoylaspartate -> dihydroortate + H2O

enzyme -> dihyrdoorotase (Cytosolic enzyme)

Front 9

what three enzymes make up CAD?

Back 9

they would Carbamoylphosphate Synthetase II, Aspartate transcarbamoylase, and Dihydroorotate

Front 10

what is the 4th reaction in pyrimidine synthesis? what is the enzyme and where is it found?

Back 10

dihydroorotate to orotate

enzyme is dihydroorotate dehydrogensae found in the Mit

Front 11

what is the 5th reaction of pyrimidine synthesis? what is the enzyme and where is it found?

Back 11

Orotate + PRPP -> OMP + PPi

enzyme is Orotate phosphoribosyl transferase

Front 12

what is the 6th reaction of pyrimidine synthesis? what is the enzyme and where is it found?

Back 12

OMP -> UMP + CO2

enzyme is OMP decarboxylase (cytosolic enzyme)

Front 13

what 2 enzymes are found on UMP synthase?

Back 13

Orotate Phosphoribosyl transferase and OMP decraboxylase

both are found in the cytosol and are UMP synthase which is a bifunctional enzyme

Front 14

What are the steps in CTP synthesis?

Back 14

UMP -> UDP -> UTP

UTP + Glutamine + ATP -> CTP + Glutamate + ADP + Pi

Front 15

what are the steps in TMP synthesis?

Back 15

UDP + NADPH + H+ -> dUDP + NADP+ + H20

dUDP -> dUMP

dUMP + N5,N10-Methylenetetrahydrofolate -> TMP + Dihydrofolate

Front 16

what is the difference between CPS II and CPS I

Back 16

1. CPS II is found in all cells; CPS I is found in the liver
2. CPS II is found is a cytosolic enzyme; CPS I is a mitochondrial enzyme
3. CPS II use glutamine as the amino doner; CPS I uses ammonium as the amino donor
4. CPS II is the primary regulator of pyrimidine nucleotide biosynthesis; it is inhibited by UDP and activated by PRPP
5. CPS I is activated during the UREA cycle and carbamoylphosphate is generated; which excretion or orotic acid in urine.

Ammonia toxicity leads to elevated levles or orotic acid in urine.

Front 17

describe in more detail Aspartate transcabarmoylase?

Back 17

this is the enzyme catalyzes the rate-limiting step in pyrimidine biosynthesis but only in prokaryotes ;

- it is an allosteric enzyme
- inhibited by CTP
-activated by ATP

Front 18

What does ribonucleotide reducatse do? What is needed for the reaction to take place?

Back 18

this converts nucleotide diphosphates NDP into corresponding deoxyribonucleotides (dNDP).
-NADPH is the ultimate reductant

-Thiroredoxin or Glutaredoxin is needed.

-Hydroxyurea the chemotherapeutic agent targets this enzyme

Front 19

What does thymidylate synthase do?

Back 19

needed to convert dUMP to TMP. N5N10 methylene tetrahydrofolate is the donor of the methyl group; it is converted into dihydrofolate

dihyrdofolate is then reduced to tetrahydrofolate with NADPH using the enzyme Dihydrofolate reductase

dihyrdofolate reductase is the target for many drugs

Front 20

Describe the degradation of pyrimidine nycleotides?

Back 20

this produces water soluble end products such as B-alanine and B aminoisobutyrate; you will see the later in urine excretion in leukemia and sever radiation exposure due to increased destruction of DNA

Front 21

What is gout? What does it cause?

Back 21

it cause by elevated plasma levels or uric acid caused by overproduction of uric acid from enhanced purine breakdown or decreased excretion of uric acid in the kidney; can also be caused high intake of dietary purines

This causes 3 things:
1. formation of monosodium urate crystals which get deposited in joints causing inflmmation and painful arthritis
2. interstitial depostion of monosodium urate crystals in the renal parenchyma
3. tophaceous depostion of monsodium urate crystals in and around the joints; the inflmmation is caused by phagocytosis of urate crystals by neutrophils leading to the production of reactive oxygen species

Front 22

what is HPRT deficiency?

Back 22

more than 98 percent loss causes Lesch-Nyhan syndrome; partial absence causes Kelley-Seegmiller Syndrome;
-Results in: hyperuricemia (lots of uric acid in the blood); gout; nephrolithiasis, renal damage, severe mental retardation and self mutilating behavoirs;

causes - the absence of HPRT leads to increased levels of hypoxanthine and guanine which are then converted into uric acid;

also leads to increased levels of PRPP which causes more purines to be produced which are converted into uric acid

Front 23

what is Adenosine Deaminase (ADA) deficiency?

Back 23

50% of pts with Severe combined immunodeficiency (SCID) have ADA deficiency.

deficiency of the enzyme leads to an increase in the cellualr levels of dATP because the enzyme also acts on deoxyadenosine. dATP is an inhibitor of ribonucleotide reductase thus inhibiting the synthesis of DNA

Front 24

what is hereditary orotic aciduria?

Back 24

results from defective de novo synthesis of pyrimidien nycleotides;
causes by mutations in UMP synthases.

pts are treated with uridine or cytidine; uridine is converted to UMP by uridine phosphotransferase. the UMP is converted to UDP and UTP which inhibits the rate limiting step enzyme carbamoylphosphate synthestase II. this basically circumvents all the earlier steps.