Variant tricarboxylic acid cycle in Mycobacterium tuberculosis: Identification of α-ketoglutarate decarboxylase

Jing Tian, Ruslana Bryk, Manabu Itoh, Makoto Suematsu, Carl Nathan

研究成果: Article

133 引用 (Scopus)

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Mycobacterium tuberculosis (Mtb) has adapted its metabolism for persistence in the human macrophage. The adaptations are likely to involve Mtb's core intermediary metabolism, whose enzymes have been little studied. The tricarboxylic acid cycle is expected to yield precursors for energy, lipids, amino acids, and heme. The genome sequence of Mtb H37Rv predicts the presence of a complete tricarboxylic acid cycle, but we recently found that α-ketoglutarate dehydrogenase (KDH) activity is lacking in Mtb lysates. Here we showed that citrate synthase, aconitase, isocitrate dehydrogenase, fumarase, malate dehydrogenase, and succinate dehydrogenase, but not KDH, are present, raising the possibility of separate oxidative and reductive half-cycles. As a potential link between the half-cycles, we found that Rv1248c, annotated as encoding SucA, the putative E1 component of KDH, instead encodes α-ketoglutarate decarboxylase (Kgd) and produces succinic semialdehyde. Succinic semialdehyde dehydrogenase activity was detected in Mtb lysates and recapitulated with recombinant proteins GabD1 (encoded by Rv0234c) and GabD2 (encoded by Rv1731). Kgd and GabD1 or GabD2 form an alternative pathway from α-ketoglutarate to succinate. Rv1248c, which is essential or required for normal growth of Mtb [Sassetti, C., Boyd, D. H. & Rubin, E. J. (2003) Mol. Microbiol 48, 77-84] is the first gene shown to encode a Kgd. Kgd is lacking in humans and may represent a potential target for chemotherapy of tuberculosis.

元の言語English
ページ(範囲)10670-10675
ページ数6
ジャーナルProceedings of the National Academy of Sciences of the United States of America
102
発行部数30
DOI
出版物ステータスPublished - 2005 7 26

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Carboxy-Lyases
Citric Acid Cycle
Mycobacterium tuberculosis
Oxidoreductases
Succinate-Semialdehyde Dehydrogenase
Fumarate Hydratase
Aconitate Hydratase
Isocitrate Dehydrogenase
Citrate (si)-Synthase
Malate Dehydrogenase
Succinate Dehydrogenase
Succinic Acid
Heme
Recombinant Proteins
Tuberculosis
Macrophages
Genome
Lipids
Amino Acids
Drug Therapy

ASJC Scopus subject areas

  • Genetics
  • General

これを引用

Variant tricarboxylic acid cycle in Mycobacterium tuberculosis : Identification of α-ketoglutarate decarboxylase. / Tian, Jing; Bryk, Ruslana; Itoh, Manabu; Suematsu, Makoto; Nathan, Carl.

:: Proceedings of the National Academy of Sciences of the United States of America, 巻 102, 番号 30, 26.07.2005, p. 10670-10675.

研究成果: Article

Tian, Jing ; Bryk, Ruslana ; Itoh, Manabu ; Suematsu, Makoto ; Nathan, Carl. / Variant tricarboxylic acid cycle in Mycobacterium tuberculosis : Identification of α-ketoglutarate decarboxylase. :: Proceedings of the National Academy of Sciences of the United States of America. 2005 ; 巻 102, 番号 30. pp. 10670-10675.
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