Biochem - Molecular (Pyrimidine & Purine Synthesis/Deficiencies & Genetic code features)

Question 1

In general, what are the 2 major steps in de novo purine synthesis?

Answer 1

(1) Start with sugar + phosphate (PRPP) (2) Add base

Question 2

In general, what are the 3 major steps in de novo pyrimidine synthesis?

Answer 2

(1) Make temporary base (orotic acid) (2) Add sugar + phosphate (PRPP) (3) Modify base

Question 3

Draw out the key reactions/steps in the de novo pyrimidine synthesis pathway, including and labeling where the following inhibitors act: (1) 5-FU (2) Hydroxyurea (3) Leflunomide (4) Impaired in orotic aciduria (5) MTX, TMP, pyrimethamine.

Answer 3

See p. 67 in First Aid 2014 for left half of visual

Question 4

Draw out the key reactions/steps in the de novo purine synthesis pathway, including and labeling where the following inhibitors act: (1) 6-MP (2) Mycophenolate, ribavirin.

Answer 4

See p. 67 in First Aid 2014 for right half of visual

Question 5

What amino acid does pyrimidine base production require?

Answer 5

Pyrimidine base production (requires aspartate)

Question 6

What 4 amino acids or other products does de novo purine base production require?

Answer 6

de novo requires aspartate, glycine, glutamine, and THF

Question 7

In pyrimidine synthesis, which kind of nucleotides are synthesized first, to what kind are they synthesized, and how?

Answer 7

Ribonucleotides are synthesized first and are converted to deoxyribonucleotides by ribonucleotide reductase

Question 8

In what 2 metabolic pathways is carbamoyl phosphate involved?

Answer 8

Carbamoyl phosphate is involved in 2 metabolic pathways: de novo pyrimidine synthesis and the urea cycle

Question 9

Name 6 antineoplastic/antibiotic drugs that function by interfering with nucleotide synthesis at different reactions.

Answer 9

(1) Leflunomide (2) Mycophenolate, Ribavirin (3) Hydroxyurea (4) 6-mercaptopurine (6-MP), Azathioprine (5) 5-fluorouracil (5-FU) (6) Methotrexate (MTX), Trimethoprim (TMP), and Pyrimethamine

Question 10

What does Leflunomide inhibit?

Answer 10

Leflunomide inhibits dihydroorotate dehydrogenase

Question 11

What does Mycophenolate inhibit? What is another drug with the same mechanism?

Answer 11

Mycophenolate and Ribavirin inhibit IMP (inosine monophosphate) dehydrogenase

Question 12

What does Hydroxyurea inhibit?

Answer 12

Hydroxyurea inhibits ribonucleotide reductase

Question 13

What does 6-MP inhibit? What is another drug with the same mechanism?

Answer 13

6-mercaptopurine (6-MP) and its prodrug Azathioprine inhibit de novo purine synthesis

Question 14

What does 5-FU inhibit? What effect does this have?

Answer 14

5-fluorouracil (5-FU) inhibits thymidylate synthase (decrease deoxythymidine monophosphate [dTMP])

Question 15

What does MTX inhibit, and in what kinds of organisms? What other 2 drugs have this same mechanism, and what kind of organisms do they affect?

Answer 15

Methotrexate (MTX), Trimethoprim (TMP), and Pyrimethamine inhibit dihydrofolate reductase (reduce dTMP) in humans, bacteria, and protozoa, respectively

Question 16

Draw the interconnected purine salvage pathways, including and labeling where each of the following act: (1) HGPRT + PRPP (2) APRT + PRPP (3) Adenosine deaminase (ADA) (4) Xanthine oxidase.

Answer 16

See p. 68 in First Aid 2014 for visual at top of page

Question 17

What are the molecular and functional effects of adenosine deaminase deficiency?

Answer 17

Excess ATP and dATP imbalances nucleotide pool via feedback inhibition of ribonucleotide reductase => prevents DNA synthesis and thus decreased lymphocyte count

Question 18

What is one of the major causes of autosomal recessive SCID?

Answer 18

Adenosine deaminase deficiency

Question 19

What defect causes Lesch-Nyhan syndrome? Give the normal reactions that are affected. What molecular effect does this have?

Answer 19

Defective purine salvage due to absent HGPRT, which converts hypoxanthine to IMP and guanine to GMP; Results in excess uric acid production and de novo synthesis

Question 20

What is the mode of inheritance of Lesch-Nyhan syndrome?

Answer 20

X-linked recessive

Question 21

What are 6 clinical findings/symptoms of Lesch-Nyhan syndrome?

Answer 21

Findings: (1) intellectual disability, (2) self-mutilation, (3) aggression, (4) hyperuricemia, (5) gout, (6) dystonia.; Think: “HGPRT: Hyperuricemia, Gout, Pissed off (aggression, self-mutilation), Retardation (intellectual disability), dysTonia”

Question 22

What defines the Unambiguous property of the genetic code?

Answer 22

Each codon species only 1 amino acid

Question 23

What defines the Degenerate/Redundant property of the genetic code? What are the exceptions to this property?

Answer 23

Most amino acids are coded by multiple codons; Exceptions: Methionine and Tryptophan encoded by only 1 codon (AUG and UGG, respectively)

Question 24

What defines the Commaless, Nonoverlapping property of the genetic code? What are the exceptions to this property?

Answer 24

Read from a fixed starting point as a continuous sequence of bases; Exceptions: some viruses

Question 25

What defines the Universal property of the genetic code? What is the exception to this property?

Answer 25

Genetic code is conserved throughout evolution; Exception in humans: mitochondria