One-Carbon Metabolism Flashcards
Be able to recognize methyl, carboxyl, formyl, and methenyl groups
methyl - CH3
carboxyl - COOH
formyl - CHO
methenyl - CH (double bond)
Biotin
1) C1 source
2) C1 group
3) Reactions
1) CO2
2) carboxyl group (COOH)
3) Carboxylations
SAM
1) C1 source
2) C1 group
3) Reactions
1) Methionine
2) Methyl group (CH3)
3) Methylations
FH4
1) C1 source
2) C1 group
3) Reactions
1) Tryptophan, Serine, and Glycine
2) formyl group, methenyl group, methylene group, and methyl group (FH4 only performs one methylation reaction)
3) Synthesis of purines, pyrimidines, and thymidine; homocysteine to methionine
Biotin is required for ____.
Carboxylases
namely: pyruvate carboxylase (pyruvate to oxaloacetate)
acetyl CoA carboxylase (produces malonyl CoA from acetyl CoA, ketone body synthesis)
propionyl CoA carboxylase (key enzyme in catabolism of branched chain amino acids)
(Also beta-methylcrotonyl CoA carboxylase which is a part of leucine catabolism)
Sources of biotin in diet
Fish, peanuts, chocolate, eggs, yeast, liver, milk, intestinal bacteria
Raw egg whites can cause biotin deficiency (avidin)
What does Biotinidase do?
It is present in cells and serum and cleaves biotin from proteins to recycle biotin. Biotinidase deficiency causes symptoms of biotin deificiency (seizures, hypotonia, ataxia)
_____ can result in encephalopathic crisis (brain damage) and hair loss.
Holocarboxylase synthetase deficiency
Holocarboxylase synthetase deficiency can result in _____.
encephalopathic crisis (brain damage) and hair loss
SAM stands for
S-Adenosylmethionine
SAM
S-Adenosylmethioine is a major carrier of methyl groups in metabolism
One carbon carriers
SAM, FH4, and Biotin
What are acceptors and products that are part of SAM methylation reactions?
Guanidoacetic acid --> creatine Phosphatidylethanolamine --> Phosphatidylcholine rRNA, tRNA --> methylated RNA Norepinephrine --> Epinephrine Protein-bound lys --> Trimethyllysine
Fate of S-Adenosyl homocysteine
Hydrolyzed to adenosine and homocysteine
Homocysteine is converted to methionine or used in cysteine synthesis.
Vitamin B12, or cobalmin, is a cofactor
FH4 stands for
tetrahydrofolate
FH4 function
Major carrier of single carbons groups in metabolism. Reduced form of folic acid
A deficiency of vitamin B9 is associated with
Spina bifida (vitamin B9 is folic acid) (if the mother is not receiving enough folic acid)
Impairment of DNA replication that affects rapidly dividing cells; macrocytic anemia, megaloblasts (oversized RBC precursors in bone marrow, subtype of macrocytic anemia)
FH4 is required for the synthesis of ___.
dTMP
Folate is converted to ____ using ____.
Tetrahydrofolate using dihydrofolate reductase. NADPH required.
Where is FH4 stored?
The liver
Folate is absorbed in its ____ form.
Monoglutamate
Where do single carbon units bind on FH4?
to the N5 and N10 sites. Carbon atoms in different oxidation states attach differently to FH4. Methyl groups bind to N5 and formyl groups bind to N10. Methenyl and methylene groups form carbon bridges between N5 and N10
Tetrahydrofolate transfers single carbon units from ______ and donates them to acceptos that are intermediates in _____.
Tryptophan, histidine, glycine, and serine as well as formaldehyde and formate (intermediates in aa degradation)
purine and pyrimidine synthesis
True or false: All FH4 derivatives are easily interconverted, reversible reactions.
Not quite true. Most are, but 5-methyl-FH4 is not.
Dietary sources of folic acid
green vegetables, yeast, liver, some fruits
A deficiency in folic acid can be caused by
alcoholism, malabsorption diseases
Antifolates are being considered as
Antitumor agents
Antifolate example
Methotrexate
Methotrexate
Antitumor agent used to treat people, analog of folic acid. Inhibits dihydrofolate reductase which converts dihydrovolate to tetrahydrofolate. 5-fluorouracil inhibits thymidylate synthase (methylation of UMP to dTMP) and it stops cell division of rapidly dividing tumor cells
Reactions dependent on vitamin B12
Homocysteine to methionine (mehtyl-cobalamin), methylmalonyl CoA to succinyl CoA (Adenosyl cobalamin)
Removes methyl from N5methyl-FH4
(Vitamin B12 is cobalamin)
How can cobalamin deficiency be detected?
Ingest radioactive Co-B12 to measure absorption
Dietary sources of B12
meat, dairy
Pathway of dietary B12 to the bloodstream
proteases release B12 from protein and it is bound by haptocorrins (R-binders). Proteases release B12 from haptocorrins and it is bound by intrinsic factor (protein), attaches to receptors and enters through the terminal segment of the small intestine (ileum)
What can happen when achlorhydia occurs?
Reduced B12 absorption (acid is required to release B12 from protein)
Vitamin B12 deficiency causes ___.
Megaloblastic anemia, neurological deterioration (pernicious anemia is B12 deficiency caused by lack of intrinsic factor)
Caused by reduced pool of tetrahydrofolate (N5methyl-FH4 cannot be converted to FH4)
Elevated methylmalonyl CoA
Hyperhomocysteinemia (symptoms)
Too much homocysteine in blood. Higher risk of coronary heart disease, stroke, periopheral vascular disease. (Increased carotid plaque thickness, associated with low B12 levels as well)
What are causes of vitamin B12 deficiency?
Vegan diet, pernicious anemia (lack of intrinsic factor), Chron’s disease (intestinal malabsorption), and bariatric surgery
What is the difference between folate deficiency and vitamin B12 deficiency?
B12 deficiency has neurological symptoms not present in folate deficiency. High methymalonyl CoA in serum may cause neurological symptoms by decreasing lipid synthesis, or might be due to decreased SAM
What are megaloblasts?
They form in bone marrow. Most are destroyed in bone marrow. Cause macrocytic anemia. DNA synthesis is inhibited (DTTP limiting due to folate deficiency) but RNA synthesis continues. RBCs appear that are abnormally large and irregular shape (macrocytes). Elevated hypersegmented neutrophils in peripheral blood are characteristic of megaloblastic anemia.
What causes hyperhomocysteinemia?
Folate deficiency, B12 deficiency, mutation in cystathione beta-synthase
Mutations in cystathione beta-synthase cause ____.
homocystinuria, a rare extreme form of hyperhomocysteinemia
Homocystinuria is caused by ____.
A mutation in cystathione beta-synthase
Symptoms of homocystinuria
eye lens dislocation, Marfan-like symptoms
Alternate pathway for homocysteine to methionine
betaine
Why are there neurological symptoms in B12 deficiency but not in folate deficiency? (possibility)
The brain does not have the betaine pathway to form methionine.
