Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0162871 (abdominal aortic aneurysm)
 8,664 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Vitamin B(12) (cobalamin) is an essential cofactor of two enzymes, methionine synthase and methylmalonyl-CoA mutase. The conversion of the vitamin to its coenzymes requires a series of biochemical modifications for which several genetic diseases are known, comprising eight complementation groups (cblA through cblH). The objective of this study was to clone the gene responsible for the cblA complementation group thought to represent a mitochondrial cobalamin reductase. Examination of bacterial operons containing genes in close proximity to the gene for methylmalonyl-CoA mutase and searching for orthologous sequences in the human genome yielded potential candidates. A candidate gene was evaluated for deleterious mutations in cblA patient cell lines, which revealed a 4-bp deletion in three cell lines, as well as an 8-bp insertion and point mutations causing a stop codon and an amino acid substitution. These data confirm that the identified gene, MMAA, corresponds to the cblA complementation group. It is located on chromosome 4q31.1-2 and encodes a predicted protein of 418 aa. A Northern blot revealed RNA species of 1.4, 2.6, and 5.5 kb predominating in liver and skeletal muscle. The deduced amino acid sequence reveals a domain structure, which belongs to the AAA ATPase superfamily that encompasses a wide variety of proteins including ATP-binding cassette transporter accessory proteins that bind ATP and GTP. We speculate that we have identified a component of a transporter or an accessory protein that is involved in the translocation of vitamin B(12) into mitochondria.
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PMID:Identification of the gene responsible for the cblA complementation group of vitamin B12-responsive methylmalonic acidemia based on analysis of prokaryotic gene arrangements. 1243 53

The finding that a lens under oxidative stress accumulated free and protein-bound cysteine (protein-S-S-cysteine) in the fiber cells prompted us to examine if there is an alternative source for cysteine pools besides the active cysteine transport system in the lens, namely, the transsulfuration pathway of homocysteine-cystathionine-cysteine, which utilises methionine through transmethylation. We examined the presence of the gene for cystathionine-beta-synthase (CBS), the rate limiting enzyme that converts homocysteine to cystathionine in the transsulfuration pathway, in human lens epithelial (HLE) B3 cells using PCR with primers designed based on the sequence of human liver CBS (Forward 5'-CCA CAC TGC CCC GGC AAA AT-3'; Reverse 5'-CTG GCA ATG CCC GTG ATG GT-3'). The purified DNA fragment (586 bp) from PCR analysis was sequenced and confirmed the homology with CBS gene from other human tissues. The CBS protein band (67 kDa) was present in the HLE cells, which reacted positively with the human liver anti-CBS antibody. The enzyme protein was detected in the pig and human lenses with the highest intensity in the epithelial layer, lower but equal quantities of CBS was present in the cortical and nuclear regions. Human nuclear CBS increased while epithelial CBS decreased with aging. Oxidative stress transiently upregulated the gene expression of CBS both in HLE cells (0.1 mMH2O2) and in pig lens cultured in TC 199 medium (0.5 mMH2O2). The catalytic activity for CBS, which was assayed by measuring the production of C14-cystathionine from C14-serine in the presence of homocysteine, S-adenosyl-methionine and pyridoxal phosphate, was detectable in the HLE cells and transiently activated with H2O2. Free cystathionine accumulated when HLE B3 cells were treated with propargylglycine (PGG), an inhibitor of cystathionase, the downstream enzyme that converts cystathionine to cysteine. More cystathionine accumulation occurred when the cells were simultaneously exposed to PGG and 0.1 mMH2O2. We have shown that oxidative stress of H2O2 could increase the flux of this transsulfuration pathway by committing more homocysteine to cysteine and glutathione production as H2O2 (0.1 mM) inhibited the remethylation enzyme of methionine synthase while concurrently activating the CBS enzyme. This is the first evidence that a transsulfuration pathway is present in the lens, and that it can be upregulated under oxidative stress to provide additional redox potential for the cells.
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PMID:The presence of a transsulfuration pathway in the lens: a new oxidative stress defense system. 1564 25