Regulation by SREBP-2 defines a potential link between isoprenoid and adenosylcobalamin metabolism.
Mevalonate kinase (MVK) catalyses an early step in cholesterol biosynthesis converting mevalonate to phosphomevalonate. Cob(I)alamin adenosyltransferase (MMAB) converts cob(I)alamin to adenosylcobalamin, functionally required for mitochondrial methylmalonyl-CoA mutase activity and succinyl-CoA formation. These two synthenic genes are found in a head-to-head formation on chromosome 12 in man and chromosome 5 in mouse. The 330bp intergenic region showed several conserved NF-Y sites indicative of potential bidirectional regulatory SREBP synergism. Both MVK and MMAB appear to be regulated in a similar manner, to a large extent by SREBP-2, since their tissue expression pattern was similar and both genes were suppressed by an excess of cholesterol as well as SREBP-2 knockdown. Statin treatment in mice upregulated both Mvk and Mmab mRNA levels indicating that this treatment may be useful in inborn errors of cblB complementation associated with methylmalonic aciduria as well as hyper IgD and periodic fever syndrome (HIDS).
Murphy
Charlotte
C
Division of Clinical Chemistry, Department of Laboratory Medicine, Karolinska Institutet at Karolinska University Hospital, 14186 Stockholm, Sweden. Charlotte.Murphy@ki.se
Murray
Ann Marie
AM
Meaney
Steve
S
Gåfvels
Mats
M
D041721:3T3-L1 Cells; D000818:Animals; D001483:Base Sequence; D003038:Cobamides / Q000378:metabolism*; D004247:DNA; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008969:Molecular Sequence Data; D011401:Promoter Regions, Genetic; D012689:Sequence Homology, Nucleic Acid; D051782:Sterol Regulatory Element Binding Protein 2 / Q000502:physiology*; D013729:Terpenes / Q000378:metabolism*
D003038:Cobamides; C497390:SREBF2 protein, human; D051782:Sterol Regulatory Element Binding Protein 2; D013729:Terpenes; D004247:DNA; C000913:cobamamide