Purine and Pyrimidine Metabolism

Question 1

Purine Structure/Ring

Answer 1

THF, Co2, Glutamine, Aspartate, Glycine

Question 2

IMP Synthesis

Answer 2

R5P (from HMP Shunt) via PRPP synthase–PRPP–PRPP via Glutamine aminotransferdase-5-phosphoribosylamine–5 phosphoribosylamine
via aspartate, glutamine, THF, Co2, Glycine–IMP

THF is a coenzyme form of B complex vitamin-Folic Acid

Question 3

ATP Synthesis from IMP

Answer 3

Aspartate portion of IMP-IMP via Adenylsuccinate synthase–Adenylsuccinate–Adenylsuccinate via Addenylsuccase–AMP–DP–ATP

Question 4

GTP synthesis from IMP

Answer 4

XMP (xanothine monophosphate) portion–IMP via IMP dehydrogenase–XMP–GMP–GDP–GTP

Question 5

PRPP Synthase activators/inhibitors

Answer 5

Activator- Pi

Inhibitors- AMP, GDP, ADP, GMP–Allosterically

Question 6

Glutamine PRPP Aminotransferdase Inhibitiors

Answer 6

AMP, GDP, ADP, GMP

Question 7

AMP and GMP Inhibitors/Promotors

Answer 7

Inhibitors-IMP

Promoters- ATP for GMP and GTP for AMP

Question 8

Methotrexate (Amethopterin)

Answer 8

Inhibitor of dihydrofolate reductase thereby prevents the formation of THF(FH4) from DHF(FH2). THF also needed to make TMP for dUMP

THF needed for 1-C of purine rings

Question 9

Trimethoprim

Answer 9

Inhibits prokaryotic dihydrofolate reductase, used as antibacterial drug.

In bacteria- inhibits enzyme dihydrofolate reductase

Question 10

Azaserine and Diazonorleucine

Answer 10

Inhibit incorporation of glutamine-nitrogen to purine ring

Question 11

6-Mercaptopurine

Answer 11

Inhibits IMP dehydrogenase and Adenylosuccinase

Question 12

Mycophenolic acid

Answer 12

Reversible inhibitor of the enzyme, IMP Dehydrogenase. Immunosuppressive drug and prevents graft rejection. Rapidly proliferates T and B lymphocytes.

Question 13

AMP Synthesis (salvage)

Answer 13

Adenine via adeinine phosphoribosyl transferase (APRT)–AMP. PRPP converted to PPi

Question 14

IMP/GMP Synthesis (salvage)

Answer 14

Hyoxanthine/Guanine via Hypoxanthine/Guanine phosphoribosyl transferase (HPGRT)–IMP/GMP. PRPP converted to PPi.

Question 15

Deoxyribonucleotide Synthesis

Answer 15

Ribonucleotide reductase with cofactor Thioredoxin. Converts any ADP, GDP, CDP, UDP, to form a dNDP form of it (dADP, dGDP, etc.

ATP activates ribonucleotide reductase and dATP inhibits it.

Question 16

Hydroxyurea

Answer 16

Interfers with ribonucleotide reductase. Used for anticancer.

Question 17

Gout

Answer 17

Mutant of hyperactive PRPP synthetase ( either with higher V max or lower Km for the substrate or failure to undergo regulation by normal feedback mechanism) – Caused due the mutation of the gene (in X-chromosome) that codes for PRPP synthetase.

HGPRTase deficinency.

G6PD defeciency- Increased diversion of glucose to Pentose P. pathway and more availability of ribose 5-P for nucleotide synthesis - more production of uric acid.

Elevation in plasma uric acid (urate) level (hyperuricemia). Leads to deposition of uric acid crystals in cartilages and joints. Such deposits are called tophi. If deposits reach synovial fluid-polymormphonuclear lucocytes. Inflammitory response and big toes. Diagnosis-urate crystals

Lactic acidosis-interference of uric acid renal clearance.

Question 18

Urolithiasis

Answer 18

Deposits of uric acid in kidney leading to stone formation

Question 19

Lesch-Nyhan syndrome

Answer 19

X-linked recessive genetic disorder with defect in HGPRT (Hypoxanthine/guanine phosphoribosyl transferase). Intellectual disability.

Question 20

Purine Nucleoside phosphorylase Deficiency

Answer 20

Autosomal recessive disorder, Immunodeficiency (Less severe). Affects only T cell immunity. Recurrent infection & neurodevelopmental delay.

Question 21

Adenosine deaminase (ADA) deficiency

Answer 21

Severe combined immunodeficiency disease (SCID). Both T-cell and B-cell functions are impaired leading to immune system failure. Autosomal recessive disorder.
Accumulation of adenosine and deoxyadenosine is the cause of immune cell dysfunction. ↑ Deoxyadenosine ↑dATP. Inhibition of ribonucleotide reductase ↓in both T & B cells

Question 22

Pyramidine Structure/Ring

Answer 22

Aspartate (3), CO2, and Glutamine

Question 23

Pyramidine Synthesis

Answer 23

Co2+Gluamine+ATP via Carbamoyl P synthetase (CPS II)–Carbamoyl phosphate–Carbamoyl phosphate via aspartate transcarbamoylase–Carbamoyl aspartate–Carbamoyl aspartate via dihydroorotase–Dihydroorotate.

Dihydroorotate via dihyroorotate dehydrogenase (only one in mitochondria) (NAD ox/redox to NADH)–Orotate–Orotate via orotate phophoribosyl transferase–Orotidylate (OMP)–Ortidylate (OMP) via OMP decarboxylase–UMP

Further nuclotide synthesis from UMP is as follows:

UMP-UDP-UTP-CTP

UMP-UDP via ribonucleotide reductase–dUDP–dUMP–dUMP via thiamidylate synthase–dTMP. Byproducts are THF and DHF.

Question 24

CPS II Inhibotrs/Activators

Answer 24

UTP-inhibits
PRPP-activates

In prokaryotes-Aspartate Trasncarbamoylase (ATC) inhibited by CTP and activated by ATP.

Question 25

5-Fluorouracil (5FU)

Answer 25

5-fluorouracil is converted into 5 fluoro dUMP (5FdUMP). 5FdUMP inactivates thymidylate synthase.

Question 26

Sulfa drugs (bacteria)

Answer 26

blocks the synthesis of folic acid in bacteria

Question 27

Orotic Aciduria

Answer 27

Deficiency of Orotate phosphoribosyl transferase and OMP decaboxylase.