One Carbon Pool
Two vitamins (folic acid and B12) can add a single carbon species to other molecules, particularly purines and pyrimidines
- involved in metabolism of four amino acids: ser, glu, his, met
- SAM (S-adenosyl methionine) is important for metabolism of biogenic amines, phospholipids
- distinct from carboxylation
Carbon species can have 5 forms:
- (1)
methyl (-CH3) – alkyl oxidation level – fully reduced
- (2)
methylene(-CH2-) – aldehyde oxidation level
- (3)
formyl(-CH=O) – acid oxidation level – oxidized
- (4)
formimino(-CH=NH) – acid oxidation level
- (5)
methenyl(-CH=) – acid oxidation level
folate can carry any of these, B12 only methyl – both can carry only one at a time
Folic Acid (Folate)
- Folate is made up of pteroic acid and glutamic acid
- humans cannot synthesize pteroic acid, so it must come from diet (i.e., it is a vitamin)
- plants and bacteria do make pteroic acid from para-aminobenzoic acid (PABA)
- PABA analogs (sulfonamides) are antibiotics
- Single carbon can be attached to N5 or N10 of folate
- methyl, formyl, formimino – attach to N5; formyl can attach to N10 sometimes; methylene and methenyl bridge N5 and N10
- Absorption
– pteroylpolyglutamate ingested; all but 1 glutamate removed in intestine, leaving folic acid (pteroylglutamate)
- dihydrofolate reductase
reduces to 7,8-dihydrofolate (DHF) then to 5,6,7,8-tetrahydrofolate (THF), using 2 NADPH
- dihydrofolate reductase is inhibited by folate analogs methotrexate and aminopterin
- these are used in treatment of cancer – prevent nucleic acid synthesis and cell replication
- THF transported in blood (by folate-binding glycoproteins), absorbed by cells, made into tetrahydropteroylpolyglutamate
- Source of the One Carbon – ultimately glucose:
– made from glucose through glycolysis (glycerate Þ hydroxypyruvate Þ serine)
Þ glycine releases a single carbon – this causes THF Þ N5,N10-CH2-THF (methylene)
- catalyzed by serine hydroxymethyl transferase and B6
(2) Glycine – from serine, ultimately from glucose
- glycine Þ CO2 + NH4+ + NADH – also causes THF Þ N5,N10-CH2-THF
Methylene can be reduced to methyl, then used to make S-adenosyl methionine
Folate Deficiency – most common vitamin deficiency in the U.S., usually alcoholic or pregnancy – no DNA synthesis
- megaloplastic anemia (low hemoglobin, large RBC’s), hypersegmented WBC nuclei, CNS effects
- can be dietary; also five congenital problems:
- (1)
no absorption
- (2)
DHF reductase deficiency
- (3)
formiminotransferase deficiency
- (4)
methylene THF reductase deficiency
- (5)
THF methyltransferase deficiency
- (6)
high levels of FIGLU (formiminoglutamate) in urine
Vitamin B12 (Cobalamin)
Vitamin B12 consists of a central cobalt atom surrounded by a planar corrin ring – complex side chain on one side
- intrinsic factor
is necessary for absorption – lack of it causes B12 deficiency and pernicious anemia
- transcobalamin
I and II are necessary for transport – transcobalamin II increases uptake by tissues
- used in transmethylation reactions (e.g., methylmalonyl CoA
Þ succinyl CoA)