title: A dodecylamine derivative of cyanocobalamin potently inhibits the activities of cobalamin-dependent methylmalonyl-CoA mutase and methionine synthase of Caenorhabditis elegans.
abstract: In this study, we showed that cyanocobalamin dodecylamine, a ribose 5'-carbamate derivative of cyanocobalamin, was absorbed and accumulated to significant levels by Caenorhabditis elegans and was not further metabolized. The levels of methylmalonic acid and homocysteine, which serve as indicators of cobalamin deficiency, were significantly increased in C. elegans treated with the dodecylamine derivative, indicating severe cobalamin deficiency. Kinetic studies show that the affinity of the cyanocobalamin dodecylamine derivative was greater for two cobalamin-dependent enzymes, methylmalonyl-CoA mutase and methionine synthase, compared with their respective coenzymes, suggesting that the dodecylamine derivative inactivated these enzymes. The dodecylamine derivative did not affect the levels of mRNAs encoding these enzymes or those of other proteins involved in intercellular cobalamin metabolism, including methylmalonyl-CoA mutase (mmcm-1), methylmalonic acidemia cobalamin A complementation group (mmaa-1), methylmalonic aciduria cblC type (cblc-1), and methionine synthase reductase (mtrr-1). In contrast, the level of the mRNAs encoding cob(I)alamin adenosyltransferase (mmab-1) was increased significantly and identical to that of cobalamin-deficient C. elegans. These results indicate that the cyanocobalamin-dodecylamine derivative acts as a potent inhibitor of cobalamin-dependent enzymes and induces severe cobalamin deficiency in C. elegans.
authors.affiliation: Division of Applied Bioresources Chemistry, The United Graduate School of Agricultural Sciences, Tottori University, Tottori 680-8533, Japan.
authors.forename: Tomohiro
authors.initials: T
authors.lastname: Bito
authors.affiliation: Division of Applied Bioresources Chemistry, The United Graduate School of Agricultural Sciences, Tottori University, Tottori 680-8533, Japan.
authors.forename: Yukinori
authors.initials: Y
authors.lastname: Yabuta
authors.affiliation: Division of Applied Bioresources Chemistry, The United Graduate School of Agricultural Sciences, Tottori University, Tottori 680-8533, Japan.
authors.forename: Tsuyoshi
authors.initials: T
authors.lastname: Ichiyanagi
authors.affiliation: Division of Applied Bioresources Chemistry, The United Graduate School of Agricultural Sciences, Tottori University, Tottori 680-8533, Japan.
authors.forename: Tsuyoshi
authors.initials: T
authors.lastname: Kawano
authors.affiliation: Division of Applied Bioresources Chemistry, The United Graduate School of Agricultural Sciences, Tottori University, Tottori 680-8533, Japan.
authors.forename: Fumio
authors.initials: F
authors.lastname: Watanabe
keywords: AdoCbl, 5′-deoxyadenosylcobalamin; C. elegans, Caenorhabditis elegans; CH3-Cbl, methylcobalamin; CN-Cbl, cyanocobalamin; Caenorhabditis elegans; Cbl, cobalamin; Cyanocobalamin; Hcy, homocysteine; IF, intrinsic factor; MCM, methylmalonyl-CoA mutase; MMA, methylmalonic acid; MMAA, methylmalonic acidemia cobalamin A complementation group; MMAB, cob(I)alamin adenosyltransferase; MMACHC, methylmalonic aciduria cblC type; MS, methionine synthase; MSR, methionine synthase reductase; Methionine synthase; Methylmalonic acid; Methylmalonyl-CoA mutase; NGM, nematode growth medium; Vitamin B12; qPCR, quantitative PCR analysis