Molecular Biochemistry (Pyrimidine Metabolim)

Question 1

Pyrimidines

Answer 1

• One ring
• Two nitrogens/four carbons; from carbamoyl phosphate and aspartate
  1- Cytidine
  2- Thymidine
  3- Uridine

Question 2

Pyrimidine synthesis

Answer 2

• Goal is to create CMP, UMP and TMP

Question 3

Pyrimidine synthesis (Step one)

Answer 3

• Make carbonyl phosphate
• Through Carbamoyl phosphate synthetase II (cytosol)
  Glutamine –> Carbamoyl phosphate
• Inhibited by UTP (uridine triphosphate)
• Ring formed first and then the ribose sugar is added

Question 4

Pyrimidine synthesis (Step two)

Answer 4

• Make Orotic acid
• Through Aspartate
  Carbamoyl phosphate –> orotic acid

Question 5

Pyrimidine synthesis (Step three)

Answer 5

• Make UMP
• Through UMP synthase and PRPP
  Orotic acid –> Uridine-MP

Question 6

Orotic aciduria (U)

Answer 6

• Autosomal recessive
• Defect in UMP synthethase
• Buildop of orotic acid
• Loss of pyrimidines
• Orotic acid in urine
• Megaloblactic anemia (not respond to B12-folate)
• Treatment: uridine (bypass the UMP synthase enzyme)

Question 7

Deficiency of ornithine transcarbamylase (OTC)

Answer 7

• OTC (ammonia into urea)
• Urea cycle enzyme
• Increase of carbomoyl phosphate
• Hight levels of ammonia –> encephalopathy

Question 8

Cytidine

Answer 8

UMP –> UTP –>CTP

Question 9

AraC

Answer 9

• Chemotherapy agent
• Mimics dCTP (pyrimidine analog)
  -Inhibits DNA polymerase

Question 10

Thymidine

Answer 10

• Only used in DNA
• Synthesized from deoxyuridine + 1 carbon
  Step 1: UMP to dUDP
  Through ribonucleotide reductase it becomes deoxyuridine-DP
  Step 2: dUDP to dUMP
  Step 3: dUMP to dTMP (critical step) through thyamidylate synthase

Question 11

Hydroxyurea

Answer 11

• Inhibits ribonucleotide reductase
• RNA intact
• Policythemia vera, essential thrombocytosis
• Increase fetal hemoglobin

Question 12

Folate

Answer 12

• Can converted into a molecule called N5, N10-tetrahydrofolate by Dihydrofolate reductase
  Folate donate a carbon –> DHF –> THF
• That carbon is donate to form TMP
• 1 carbon carriers

Question 13

5-FU (5-fluoracil)

Answer 13

• Inhibit Thymidylate Synthase
• Chemotherapy angent that mimics uracil (5- dUMP abnormal dUMP)
• Blocks dTMP synthesis

Question 14

Methotrexate (chemotherapy angent and immunosuppressant)

Answer 14

• Mimics DHF
• Inhibit dihyrofolate reductase
• Block synthesis dTMP
• Bone marrow suppression –> rescued with Leucorovin (colonic acid) THF inside

Question 15

Sulfonamides antibiotics

Answer 15

• Bacteria can’t absorb folic acid they synthesize THF from PABA (para-aminobenzoic acid)
• Sulfonamides mimics PABA
• Block THF synthesis in bacterias

Question 16

Folate deficiency

Answer 16

• Loss of dTMP production –> loss DNA production
• Macrocytic anemia
• Neural tube defect in pregnancy
• NO NEUROLOGICAL DYSFUNCTION

Question 17

Vitamin B12

Answer 17

• Plays a role in convertion of dUridine-MP to Thymidine-MP
• Use N5-Methyl THF from N5,N10 THF to regenerate back THF
• Deficiency cause Methyl folate trap
• Loss of dTMP synthesis (megaloblastic anemia)
• Neurological dysfunction(demyelination)

Question 18

Homocysteine and MMA (methylmalonic acid)

Answer 18

• Use to diagnose Folate vs B12 deficiency
• Both deficiency of folate or B12 cause increase of homocysteine
• B12 converts MethymlonyCoA (from MMA) into SuccinylCoA
• Only on deficiency of B12 due to increase of MMA

Question 19

Megaloblastic anemia

Answer 19

• Decrease in Hct
• Large RBCs
• Increase MCV
• Hypersegmented neutrophils
• Due to defective DNA production