ABSTRACT
Alkynylcorrinoids are a class of organometallic B12 derivatives, recently rediscovered for use as antivitamins B12 and as core components of B12-based biological vectors. They feature exceptional photochemical and thermal stability of their characteristic extra-short Co-C bond. We describe here the synthesis and structure of 3-hydroxypropynylcobalamin (HOPryCbl) and photochemical experiments with HOPryCbl, as well as of the related alkynylcobalamins: phenylethynylcobalamin and difluoro-phenylethynylcobalamin. Ultrafast spectroscopic studies of the excited state dynamics and mechanism for ground state recovery demonstrate that the Co-C bond of alkynylcobalamins is stable, with the Co-N bond and ring deformations mediating internal conversion and ground state recovery within 100 ps. These studies provide insights required for the rational design of photostable or photolabile B12-based cellular vectors.
Subject(s)
Carbon/chemistry , Cobalt/chemistry , Vitamin B 12/chemistry , Crystallography, X-Ray , Density Functional Theory , Models, Molecular , Molecular Conformation , Photochemical Processes , Temperature , Vitamin B 12/analogs & derivatives , Vitamin B 12/chemical synthesisABSTRACT
B12 antivitamins are important and robust tools for investigating the biological roles of vitamin B12 . Here, the potential antivitaminâ B12 2,4-difluorophenylethynylcobalamin (F2PhEtyCbl) was prepared, and its 3D structure was studied in solution and in the crystal. Chemically inert F2PhEtyCbl resisted thermolysis of its Co-C bond at 100 °C, was stable in bright daylight, and also remained intact upon prolonged storage in aqueous solution at room temperature. It binds to the human B12 -processing enzyme CblC with high affinity (KD =130â nm) in the presence of the cosubstrate glutathione (GSH). F2PhEtyCbl withstood tailoring by CblC, and it also stabilized the ternary complex with GSH. The crystal structure of this inactivated assembly provides first insight into the binding interactions between an antivitamin B12 and CblC, as well as into the organization of GSH and a base-off cobalamin in the active site of this enzyme.
Subject(s)
Glutathione/chemistry , Vitamin B 12/antagonists & inhibitors , Catalytic Domain , Crystallography, X-Ray , Fluorine/chemistry , Humans , Hydrolysis , Kinetics , Models, Molecular , Molecular Structure , Spectrum Analysis/methods , Substrate Specificity , Temperature , Vitamin B 12/chemistry , Vitamin B 12/pharmacologyABSTRACT
The crystal structures of three salts of anionic 5-aminotetrazole are described. The tetramethylammonium salt (P[Formula: see text]) forms hydrogen-bonded ribbons of anions which accept weak C-Hâ¯N contacts from the cations. The cystamine salt (C2/c) shows wave-shaped ribbons of anions linked by hydrogen bonds to screw-shaped dications. The tetramethylguanidine salt (P21/c) exhibits layers of anions hydrogen-bonded to the cations.
ABSTRACT
Don't take this antivitamin! 2-Phenylethynylcobalamin was prepared in a newly developed radical reaction using cob(II)alamin and 1-iodo-2-phenylethyne. It has an exceptionally short organometallic bond and is a remarkably light-stable and heat-resistant organometallic cobalamin. It is bound well by two important proteins of the human B12 transport system and has properties that are as expected for a new type of an "antivitaminâ B12 ".
