Bitte logge Dich ein, um diesen Artikel zu bearbeiten. Serum or plasma vitamin B12 concentrations may be of limited value in assessing cobalt status because of the presence of B12 analogs in bovine blood. In methylmalonyl-CoA mutase, the β-axial ligand 5’-deoxy-5’-adenosine reversibly dissociated to give the deoxyadenosyl radical. Methylmalonyl-CoA mutase (MCM), mitochondrial, also known as methylmalonyl-CoA isomerase, is a protein that in humans is encoded by the MUT gene. Copyright © 2020 American Society for Microbiology | Privacy Policy | Website feedback, Print ISSN: 0021-9193; Online ISSN: 1098-5530, Institute for Structural Biology and Drug Discovery and Department of Medicinal Chemistry, Virginia Commonwealth University, Richmond, Virginia 23219, Sign In to Email Alerts with your Email Address. Treatment with vitamin B12 injections was initiated on day 28. There were no neurological symptoms. In the case of anicm meaA mutant, these decreased pools significantly reduce monensin titers. A strict vegetarian woman consumed a plant-based diet for 8 years. 1) involving reduction to butyryl-CoA, isomerization to isobutyryl-CoA, and subsequent oxidation (38, 44). A multitude of labeling studies carried out with isobutyrate, butyrate, and ethyl acetoacetate, in this and previous studies of S. cinnamonensis, have consistently shown significantly greater labeling of the butyryl-CoA (ethylmalonyl-CoA)-derived position of monensin A than the methylmalonyl-CoA-derived positions. Bacterial strains, plasmids, and cultural conditions. The patient was extremely pale. By contrast, less information is available on the enzymes and pathways that provide the required biosynthetic precursors for these processes. The energy of the magnetic interaction between cob(II)alamin and the free radical at the active site of MCM is 4000 G (0.37 cm−1) or 1 cal mol−1 (G. H. Reed, personal communication). collinus (15) have indicated that MeaA is neither an MCM nor an ICM. by the National Institutes of Health (Grant GM50541) and Eli Lilly & Company. Folate treatment does not, however, reverse the neurological problems. Strong13C doublets surrounding the natural abundance signal for both C-32 and C-33 of monensin A were observed (Fig.5) for the WM2 mutant, which indicated the simultaneous presence of a 13C label at both carbons. Monensins were isolated and quantitated by high-performance liquid chromatography (HPLC) analysis as described previously (34). The meaA mutant produced a significantly higher monensin A-to-monensin B ratio (4:1) compared to the C730.1 strain (1:1) in either production media. Thus, the MeaA substrate might also contain two oxidized and possibly carboxylated substituents, with one activated as a CoA thioester. Zwei dieser Ketten lagern sich zu einem Homodimer zusammen, das dann zwei Moleküle Adenosylcobalamin (AdoB12) als Cofaktor bindet und so das aktive Holoenzym bildet. In mammalian mitochondria, the enzyme is required for the degradation of odd-chain fatty acids and branched-chain amino acids through the conversion of methylmalonyl-CoA to succinyl-CoA. ScienceDirect ® is a registered trademark of Elsevier B.V. ScienceDirect ® is a registered trademark of Elsevier B.V. URL:, URL:, URL:, URL:, URL:, URL:, URL:, URL:, URL:, Enzymes, Enzyme Mechanisms, Proteins, and Aspects of NO Chemistry, Methylmalonic acidemia is caused by a deficiency in, Nutritional Biochemistry (Second Edition), MMA accumulates in the bloodstream and urine in genetic diseases involving mutations in, “A warning regarding the use of folic acid,” 1947, Encyclopedia of Food Sciences and Nutrition (Second Edition), is used in the body as a cofactor for several essential enzymatic reactions, including methionine synthesis and, Elizabeth H. Jeffery, ... M.E. Roberts, in Encyclopedia of Food Sciences and Nutrition (Second Edition), 2003. The meaA and ORF1 ORFs are both preceded by a potential streptomycete ribosome binding sequence, GGAG, at nucleotides 107 to 110 and 2134 to 2137, respectively (4). Furthermore, expression of either of these genes can be used to restore monensin production in a meaA icm mutant (WD2) to at least wild-type levels. Cattle fed adequate cobalt have sufficient vitamin B12 stored in their liver to last for several months even if they are abruptly switched to a cobalt-deficient diet. Sie ist ein Thioester aus Coenzym A und Methylmalonsäure sowie eine Carbonsäure. Role of methylmalonyl-CoA in polyketide biosynthesis.The identification of numerous gene clusters involved in polyketide antibiotics has led to a better understanding of the genetic and biochemical elements governing the biosynthesis of these compounds (2, 20). PA is a risk factor for certain cancers of the stomach. Targeted disruption of S. cinnamonensis meaA and phenotype analysis.An insertional inactivation strategy was used to disrupt the meaA gene in both S. cinnamonensis C730.1 and the icm mutant (44). MeaA from S. cinnamonensis showed the highest amino acid sequence identity to corresponding proteins in S. coelicolor (89%),S. collinus (90%), and M. extorquens(60%). In this case, the monensin titers were increased almost twofold (relative to those of either the C730.1 or meaA mutant) and the monensin A-to-monensin B ratio switched from 4:1 to 1:5. The substrate, L-methylmalonyl-CoA hydrolyzes to form methylmalonate (methylmalonic acid), a neurotoxic dicarboxylic acid that, due to the poor dicarboxylic acid transport capacities of the blood-brain barrier, is effectively trapped within the CNS, leading to neurological debilitation. The TC–Cbl complex is internalized by carrier-mediated endocytosis mediated by the transcobalamin receptor (TCblR)3 and is initially processed in the lysosome, where TC undergoes proteolytic degradation. Psychiatric signs of unclear pathogenesis are present, but there is also neurological degeneration, characterized by myelinic vacuolation of axons in both ascending and descending tracts (especially of the pyramidal tracts). cinnamonensis wild-type strains has recently been found to increase both the overall monensin titers and the amount of monensin B relative to that of monensin A (49). Fatty acid analyses.It has previously been shown that alterations in the levels of butyryl-CoA or isobutyryl-CoA pool can directly alter the types and amounts of branched-chain and straight-chain fatty acids in streptomycetes (45). The resultant free radical undergoes isomerization by internal cyclization to the oxycyclopropyl radical, which opens to the succinyl-CoA radical, as in the chemical counterpart of Figure 24. Restoration of monensin titers can be accomplished by plasmid-based expression of genes encoding either MeaA or MCM. Methylmalonyl-CoA mutase is present in both mammals and bacteria. The same conclusion was reached by generating ameaA mutant of S. cinnamonensis and observing that it made significantly higher ratios of monensin A compared to monensin B. Methylmalonic acidemia is caused by a deficiency in methylmalonyl-CoA mutase, which functions in the conversion of methionine, isoleucine, and valine to succinyl-CoA (see Fig. Synonyme: Methylmalonyl-Coenzym A, MMl-CoA. Elizabeth H. Jeffery, ... M.E. Das Protein wird durch das MUT-Gen kodiert. Role of MeaA in providing methylmalonyl-CoA.The role ofmeaA in providing methylmalonyl-CoA for monensin biosynthesis was studied by two approaches. Cloning and sequence analysis of S. cinnamonensis meaA.The plasmid pHL1 (24), containing theccr gene and 0.5 kb of meaA of S. cinnamonensis, was used as the DNA probe to screen a cosmid library. 1987; Carmel and Johnson, 1978). 3 shows the result of a binding site comparison between three mycobacterial MeaB structures and the human MMAA. Darüber hinaus kommt es im Herz, in den Ovarien, im ZNS, in den Muskeln, in der Leber sowie in geringerem Umfang in der Milz vor. To combat these effects perioperative anti-catabolic regimes and no diet discontinuation are recommended. The double-crossover event in both these clones ware confirmed by PCR using primers 1 and 2 (see Materials and Methods). In Propionibaterium shermanii, the enzyme is required for the fermentation of pyruvate to propionate. Hence, the role of coenzyme B-12 in the catalytic process is that of a reversible generator of a free radical. This gene contains two ORFs (designated the mutB and icmA genes, respectively) encoding 531 and 159 residues, respectively, which are similar in size to IcmA and IcmB of both S. cinnamonensis and S. coelicolor (33, 48). John W. Pelley PhD, in Elsevier's Integrated Biochemistry, 2007. The levels of methylmalonyl-CoA were limiting, however, in the icm meaA mutant (WD2), which produced only 10% of the monensin titers (predominantly as monensin A) seen with either the C730.1 meaA or icm mutants in either carbohydrate-based or oil-based media. A child will not show symptoms of anemia until the age of 2 years, indicating that the amount of vitamin present at birth can fulfill the child's needs for this period. The working conditions for optimal separation were obtained in order to … Copyright © 2020 Elsevier B.V. or its licensors or contributors. The MCM reaction mechanism begins with homolytic cleavage of AdoB12's C-Co(III) bond, the C and Co atoms each acquire one of the electrons that formed the cleaved electron pair bond. When grown in either a carbohydrate-based medium or an oil-based medium, the mutants WM2 (meaA mutation) and WD2 (icm and meaA mutations) and wild-type C730.1 strains grew equally well and displayed no morphological differences.