Methylation reactions in biological systems: Vitamin B12 metabolism- Lecture 75

Question 1

What is the importance of methionine?

Answer 1

protein synthesis
major biological methylating agent used in synthesis of many important biochemicals (methionine produces SAM in the methionine adenozyl transferase reaction)

Question 2

How is SAM synthesized?

Answer 2

Met + ATP –> SAM + 3Pi

via methionine adenosyltransferase

Question 3

How is methionine regenerated from SAM?

Answer 3

(i) SAM –> S-Adenosyl homocysteine (SAH)
via donation reaction with another compound
(ii) SAH + H2O –> adenosine + homocysteine
via hydrolysis
(iii) homocysteine + Methyl-Folic Acid –> methionine + tetrahydrofolate (folic acid)
via homocysteine methyltransferase and a vitamin B12 cofactor

Question 4

What regulates the methionine regeneration reaction?

Answer 4

high levels of methionine inhibit the reaction

Question 5

What is the fate of homocysteine if sufficient methionine is present?

Answer 5

homocysteine + serine –> cystathionine + H2O
via cystathionine synthase with a PLP cofactor
cystathionine –> cysteine + alpha ketobutyrate
via cystathionase with a PLP cofactor

Question 6

What regulates the conversion of homocysteine to cystathionine?

Answer 6

high levels of cysteine inhibit cystathionine synthase

Question 7

What is homocystinuria?

Answer 7

an inborn error of metabolism in which large amounts of homocysteine accumulate –> neurological disorders, failure to grow and thrive, skeletal abnormalities, arthritis, and cardiovascular abnormalities

Question 8

What are the causes of homocystinuria?

Answer 8

normally caused by cystathionine synthase deficiency
can be caused by methionine synthase deficiency
vitamin B12 deficiency
folate deficiency
PLP deficiency

Question 9

How is homocystinuria treated?

Answer 9

if vitamin deficient- supplement

if other- limit Met in diet (hard due to it being an essential aa) and add Cys into diet

Question 10

What is the structure of B12?

Answer 10

one corrin ring (composed of 4 pyrrole rings linked to each other) plus a central atom of cobalt

Question 11

What is the resting state of B12?

Answer 11

the 6th substituent of the cobalt is an OH (hydroxycobalamine)

Question 12

What is the vitamin form of B12?

Answer 12

cyanide is in the 6th position of the cobalt (cyanocobalamine) (replaced with OH during digestion)

Question 13

What is the vitamin cofactor form of B12?

Answer 13

6th substituent is a methyl (methylcobalamine) or deoxyadenosine group (deoxyadenosyl cobalamine)

Question 14

How is methylcobalamine synthesized?

Answer 14

Hydroxycobalamine accepts CH3 group from N5-CH3-THF to form methylcobalamine (used as cofactor for homocysteine –> Met reaction)

Question 15

How is deoxyadenosyl cobalamine synthesized?

Answer 15

B12 + ATP –> deoxyadenosyl cobalamine + 3Pi via deoxyadenosyl transferase (methylmalonyl mutase reaction cofactor)

Question 16

Which amino acids can be broken down to form propionyl CoA?

Answer 16

isoleucine, valine, methionine, and threonine

as well as odd chain fatty acids

Question 17

What is methylmalonyl aciduria?

Answer 17

accumulation of MMA (a powerful acid) causing GI irritation, emesis, CNS disturbances, convulsitons, intellectual disability, and death (by the age of two)
about 0.5 per 100,000

Question 18

What causes methylmalonyl aciduria?

Answer 18

MMS mutase deficiency
B12 deficiency
deoxyadenosyl transferase (which makes deoxyadenosyl B12- rare)

Question 19

How do you treat methylmalonyl aciduria?

Answer 19

If cause is vitamin deficiency- supplement

If cause is other- treat with decreased Met, Val, Thr, and Ile in diet (all essential acids so difficult to do)