Transcript 15-Tetrahydrofolate-and-B12

The role of tetrahydrofolate in biosynthetic
reactions
© Michael Palmer 2014
Folic acid is reduced by dihydrofolate reductase
(DHFR)
© Michael Palmer 2014
Sources and destinations of C1 units transferred by
tetrahydrofolic acid
Sources:
1. serine, glycine
2. histidine, tryptophan
Biosynthetic destinations:
1. purine bases
2. thymine
3. S-adenosylmethionine → choline phospholipids, creatine,
epinephrine, DNA methylation
The serine hydroxymethyltransferase reaction:
release of CH2O
© Michael Palmer 2014
Capture of formaldehyde by THF yields N,N′methylene-THF
© Michael Palmer 2014
N,N′-methylene-THF production by the glycine
cleavage system
© Michael Palmer 2014
Histidine degradation produces N,N′-methenyl-THF
© Michael Palmer 2014
Redox transitions between various forms of C1THF
© Michael Palmer 2014
Overview of flux through the C1-THF pool
© Michael Palmer 2014
Folate antimetabolites as antimicrobials
© Michael Palmer 2014
Structure of methylcobalamin
© Michael Palmer 2014
The S-adenosylmethionine (SAM) cycle requires
vitamin B12
© Michael Palmer 2014
Structures of S-adenosylmethionine and Sadenosylhomocysteine
© Michael Palmer 2014
SAM-dependent methylation reactions
1. methylation of phosphatidylethanolamine (PE) to
phosphatidylcholine (PC)
2. guanidinoacetate → creatine
3. norepinephrine → epinephrine
4. acetylserotonin → melatonin
5. DNA methylation
6. methylation of drugs (e.g. mercaptopurine)
Phosphatidylethanolamine methylation
© Michael Palmer 2014
Sphingomyelin acquires its phosphocholine
headgroup from PC
© Michael Palmer 2014
Major nerve fibers are myelinated
© Michael Palmer 2014
Creatine metabolism
© Michael Palmer 2014
Uptake, transport and storage of folic acid
●
contained in vegetables (Latin folium = leaf)
●
synthesized by bacterial flora in the large intestine
●
active transport mediates intestinal uptake and renal reuptake,
as well as accumulation in the liver
●
50% of all folate is stored in the liver
Causes of folate deficiency
●
inflammatory bowel diseases
●
surgical bowel resection (short intestine syndrome)
●
cytochrome P450-inducing drugs
●
excessive alcohol consumption—contentious
Folate deficiency causes macrocytic anemia
© Michael Palmer 2014
Intestinal uptake of vitamin B12
© Michael Palmer 2014
Various causes of B12 deficiency
© Michael Palmer 2014
Disruption of folate-dependent metabolism by
vitamin B12 deficiency: the methyl trap hypothesis
© Michael Palmer 2014