Maple syrup urine disease. Complete primary structure of the E1 beta subunit of human branched chain alpha-ketoacid dehydrogenase complex deduced from the nucleotide sequence and a gene analysis of patients with this disease.

Nobukuni, Yoshitaka; Mitsubuchi, Hiroshi; Endo, Fumio; Akaboshi, Izumi; Asaka, Jun-ichiro; Matsuda, Ichiro

doi:10.1172/jci114690

Cited by 30 publications

(5 citation statements)

References 42 publications

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“…gene is located at chromosomal position 19q13.1-13.2 and consists of 9 exons which encode a 1.6 kb mRNA, translated into a 378-aa protein with a 45-aa leader sequence (Zhang et al 1988). The E1" gene is located at chromosomal position 6q14 and consists of 11 exons, which encode a 1.4 kb mRNA, translated into a 342-aa protein with a 50-aa leader sequence (Chuang et al 1996;Nobukuni et al 1990). E2, or dihydrolipoamide branched-chain transacylase, is a dihydrolipoyl transacylase that exists as a homo-24-mer with octagonal symmetry in the BCKDH complex, and is the functional Fcore_ of the enzyme complex (Chuang and Shih 2001).…”

Section: Molecular Genetics Of the Bckdh Complexmentioning

confidence: 99%

Animal models of maple syrup urine disease

Skvorak

2009

J of Inher Metab Disea

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Maple syrup urine disease (MSUD) is an inherited aminoacidopathy resulting from dysfunction of the branched-chain keto acid dehydrogenase (BCKDH) complex. This disease is currently treated primarily by dietary restriction of branched-chain amino acids (BCAAs). However, dietary compliance is often challenging. Conversely, liver transplantation significantly improves outcomes, but donor organs are scarce and there are high costs and potential risks associated with this invasive procedure. Therefore, improved treatment options for MSUD are needed. Development of novel treatments could be facilitated by animal models that accurately mimic the human disease. Animal models provide a useful system in which to explore disease mechanisms and new preclinical therapies. Here we review MSUD and currently available animal models and their corresponding relevance to the human disorder. Using animal models to gain a more complete understanding of the pathophysiology behind the human disease may lead to new or improved therapies to treat or potentially cure the disorder.

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Section: Molecular Genetics Of the Bckdh Complexmentioning

confidence: 99%

Animal models of maple syrup urine disease

Skvorak

2009

J of Inher Metab Disea

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“…(A) Similarities of the C. magnum AoDH El1 subunit to other proteins. The amino acid sequence of C. magnum AoDH E13 was compared with the primaiy structures of proteins stored in the SWISSPROT data library (11,29,32,35,48,49,51,57,77,81) by using the program FASTA (17). (B) Phylogenetic tree for the AoDH Elt subunits and the E13 subunits of 2-oxo acid dehydrogenase complexes from different relevant sources.…”

Section: Vmentioning

confidence: 99%

Biochemical and molecular characterization of the Clostridium magnum acetoin dehydrogenase enzyme system

et al. 1994

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E2 (dihydrolipoamide acetyltransferase) and E3 (dihydrolipoamide dehydrogenase) of the Clostridium magnum acetoin dehydrogenase enzyme system were copurified in a three-step procedure from acetoin-grown cells. The denatured E2-E3 preparation comprised two polypeptides with M(r)s of 49,000 and 67,000, respectively. Microsequencing of both proteins revealed identical amino acid sequences. By use of oligonucleotide probes based on the N-terminal sequences of the alpha and beta subunits of E1 (acetoin dehydrogenase, thymine PPi dependent), which were purified recently (H. Lorenzl, F.B. Oppermann, B. Schmidt, and A. Steinbüchel, Antonie van Leeuwenhoek 63:219-225, 1993), and of E2-E3, structural genes acoA (encoding E1 alpha), acoB (encoding E1 beta), acoC (encoding E2), and acoL (encoding E3) were identified on a single ClaI restriction fragment and expressed in Escherichia coli. The nucleotide sequences of acoA (978 bp), acoB (999 bp), acoC (1,332 bp), and acoL (1,734 bp), as well as those of acoX (996 bp) and acoR (1,956 bp), were determined. The amino acid sequences deduced from acoA, acoB, acoC, and acoL for E1 alpha (M(r), 35,532), E1 beta (M(r), 35,541), E2 (M(r), 48,149), and E3 (M(r), 61,255) exhibited striking similarities to the amino acid sequences of the corresponding components of the Pelobacter carbinolicus acetoin dehydrogenase enzyme system and the Alcaligenes eutrophus acetoin-cleaving system, respectively. Significant homologies to the enzyme components of various 2-oxo acid dehydrogenase complexes were also found, indicating a close relationship between the two enzyme systems. As a result of the partial repetition of the 5' coding region of acoC into the corresponding part of acoL, the E3 component of the C. magnum acetoin dehydrogenase enzyme system contains an N-terminal lipoyl domain, which is unique among dihydrolipoamide dehydrogenases. We found strong similarities between the AcoR and AcoX sequences and the A. eutrophus acoR gene product, which is a regulatory protein required for expression of the A. eutrophus aco genes, and the A. eutrophus acoX gene product, which has an unknown function, respectively. The aco genes of C. magnum are probably organized in one single operon (acoABXCL); acoR maps upstream of this operon.

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“…At the molecular level, the cDNA for four of the enzymes producing the multienzyme BCKD complex have been cloned (32)(33)(34)(35). The E2 cDNA has produced stably transfected fibroblasts from an E2-MSUD patient and could be placed in retroviral vectors suitable for hepatic or muscle cell transfection and autologous transplantation (36).…”

Section: Resultsmentioning

confidence: 99%