Abstract:phy, paper chromatography and electrophoresis, and by amidation of the analog to 5 '-deoxyadenosylcobalamin. The following substituted amides of 5 '-deoxyadenosylcobalamin were prepared cla the carboxylic acid analog: the methylamide, ethylamide, anilide, and 2,4-dinitroanilide. These analogs had similar spectra to 5'-deoxyadenosylcobalamin, but differing pK" values, and whereas I was neither active nor inhibitory in the ribonucleotide reductase system from Lactobacillus leichmannii, the other analogs were act… Show more
“…It was speculated that steric effects and/or lack of hydrogen-bond donation from the analogues formed a "looser" complex with the apoenzyme making the breakage of the Co-C bond less energetically favorable. The interpretation of this and other experiments (Morley et al, 1968;Yakusheva et al, 1977;Kensley et al 1978;Lien et al, 1974; Ellenbogen, 1975) involving the modification of the propionamide side chains depends on the assignment of the three cyanocobalaminmonocarboxylic acid isomers that are used as a starting point for further modifications.…”
mentioning
confidence: 77%
“…The results of any studies before 1980 using the CNCbl monocarboxylic acids or derivatives made from them can now be reinterpreted with the correct structural assignments of the isomers. These studies include determination of the activities of coenzyme B12 analogues modified at the propionamide side chains in the enzymes diol dehydrase (Toraya et al, 1979), ribonucleotide reductase (Morley et al, 1968), and glycerol (Bratt & Hogenkamp, 1984) are given in parentheses.…”
Section: Discussionmentioning
confidence: 99%
“…In the ribonucleotide reductase study (Morley et al, 1968) the ¿-monocarboxylic acid (formerly identified as the e isomer) of coenzyme B12 and derivatives made from the acid were used.…”
The three cyanocobalaminmonocarboxylic acid isomers known to be produced by the mild acid hydrolysis of the b-, d-, and e-propionamide side chains of vitamin B12 have been unambiguously assigned by modern 2D NMR methods. Previously, structural assignments had been made by less definitive NMR methods, and both X-ray and neutron diffraction studies had failed to locate unambiguously the position of the carboxyl group. The b and e isomers were structurally assigned in this study, on the basis of the assignment of the 13C NMR signal of the carboxyl group from HMBC (1H-detected heteronuclear multiple-bond correlation) spectra. The carboxyl group resonances exhibited the greatest changes in chemical shift between the protonated (pH 2) and deprotonated (pH greater than 7) forms of the acids. The d isomer was assigned by difference. Since the HMBC experiments required the assignments of side-chain CH2 signals, homonuclear Hartmann-Hahn, 2D homonuclear correlation, 2D nuclear Overhauser effect, 1H-detected heteronuclear multiple quantum coherence, and HMBC spectroscopies were used to assign completely the 1H and 13C NMR spectra of the b and e isomers at pH approximately 7. By comparison with the 13C NMR spectra of the b and e isomers, nearly one-fourth of the resonances of the 13C NMR spectrum of vitamin B12 have been reassigned. The sites of incorporation of 13C-labeled precursors in B12 biosynthesis found in previous studies have been verified by a comparison of 13C assignments. The results of studies using cobalamins modified at the b-, d-, and e-propionamide side chains in which the incorrect structural assignments were used (before 1980), particularly studies of B12-dependent enzymes, require reinterpretation using the correct structural assignments.
“…It was speculated that steric effects and/or lack of hydrogen-bond donation from the analogues formed a "looser" complex with the apoenzyme making the breakage of the Co-C bond less energetically favorable. The interpretation of this and other experiments (Morley et al, 1968;Yakusheva et al, 1977;Kensley et al 1978;Lien et al, 1974; Ellenbogen, 1975) involving the modification of the propionamide side chains depends on the assignment of the three cyanocobalaminmonocarboxylic acid isomers that are used as a starting point for further modifications.…”
mentioning
confidence: 77%
“…The results of any studies before 1980 using the CNCbl monocarboxylic acids or derivatives made from them can now be reinterpreted with the correct structural assignments of the isomers. These studies include determination of the activities of coenzyme B12 analogues modified at the propionamide side chains in the enzymes diol dehydrase (Toraya et al, 1979), ribonucleotide reductase (Morley et al, 1968), and glycerol (Bratt & Hogenkamp, 1984) are given in parentheses.…”
Section: Discussionmentioning
confidence: 99%
“…In the ribonucleotide reductase study (Morley et al, 1968) the ¿-monocarboxylic acid (formerly identified as the e isomer) of coenzyme B12 and derivatives made from the acid were used.…”
The three cyanocobalaminmonocarboxylic acid isomers known to be produced by the mild acid hydrolysis of the b-, d-, and e-propionamide side chains of vitamin B12 have been unambiguously assigned by modern 2D NMR methods. Previously, structural assignments had been made by less definitive NMR methods, and both X-ray and neutron diffraction studies had failed to locate unambiguously the position of the carboxyl group. The b and e isomers were structurally assigned in this study, on the basis of the assignment of the 13C NMR signal of the carboxyl group from HMBC (1H-detected heteronuclear multiple-bond correlation) spectra. The carboxyl group resonances exhibited the greatest changes in chemical shift between the protonated (pH 2) and deprotonated (pH greater than 7) forms of the acids. The d isomer was assigned by difference. Since the HMBC experiments required the assignments of side-chain CH2 signals, homonuclear Hartmann-Hahn, 2D homonuclear correlation, 2D nuclear Overhauser effect, 1H-detected heteronuclear multiple quantum coherence, and HMBC spectroscopies were used to assign completely the 1H and 13C NMR spectra of the b and e isomers at pH approximately 7. By comparison with the 13C NMR spectra of the b and e isomers, nearly one-fourth of the resonances of the 13C NMR spectrum of vitamin B12 have been reassigned. The sites of incorporation of 13C-labeled precursors in B12 biosynthesis found in previous studies have been verified by a comparison of 13C assignments. The results of studies using cobalamins modified at the b-, d-, and e-propionamide side chains in which the incorrect structural assignments were used (before 1980), particularly studies of B12-dependent enzymes, require reinterpretation using the correct structural assignments.
“…1 A second important characteristic distinguishing the class I and class II enzymes is their specificity for AdoCbl. The class II enzymes, including ribonucleotide reductase [21][22][23][24], diol dehydratase [25][26][27][28][29][30][31], and glycerol dehydratase [32], are remarkably promiscuous in tolerating structural alterations in the coenzyme. A large number of analogs with structural alterations in the adenine and ribose moieties [23][24][25][26][27]31,32], the corrin and its side chains [22,25,31,32], and the axial nucleotide [21,25,[28][29][30][31][32] are partially active coenzymes with these enzymes (although others are inactive and are inhibitors).…”
“…The six carboxamide corrin ring substituents provide polar hydrogen bond donating and accepting functionalities which are potential points of binding interactions with the various types of proteins that bind Cbls. Analogs with structurally altered peripheral substituents have consequently been used to study the structural basis of Cbl binding to vitamin B 12 binding proteins, − vitamin B 12 transport receptors, , and 5‘-deoxyadenosylcobalamin- (AdoCbl 1 -) requiring enzymes. − In addition, recent work has suggested that steric interference with side chain thermal motions by the organic ligand of RCbls can provide significant entropic driving force for cleavage of the Co−C bonds in such complexes . Analogs of CNCbl 1 ( 1 ) in which the b , c , d , or e amide side chain is hydrolyzed to a carboxylic acid are well-known and well-characterized, ,− as are the N -alkyl amides and alkyl esters produced from them. ,, …”
Treatment of the c-monocarboxylate of
cyanocobalamin with diphenylphosphoryl azide affords the
c-NH2 derivative in moderate yield along with a
novel green corrinoid. The latter is also obtained when the amine
is treated with aqueous base. A single-crystal X-ray diffraction
analysis shows that the green corrinoid lacks a c side chain
and contains a C7−C8 double bond indicating that the B pyrrole ring
has been aromatized.
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