{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,4]],"date-time":"2026-10-04T05:21:46Z","timestamp":1791091306945,"version":"4.1.0"},"reference-count":46,"publisher":"Portland Press Ltd.","issue":"1","content-domain":{"domain":["portlandpress.com"],"crossmark-restriction":true},"short-container-title":[],"published-print":{"date-parts":[[2006,11,15]]},"abstract":"<jats:p>The BCKDH (branched-chain \u03b1-keto acid dehydrogenase complex) catalyses the rate-limiting step in the oxidation of BCAAs (branched-chain amino acids). Activity of the complex is regulated by a specific kinase, BDK (BCKDH kinase), which causes inactivation, and a phosphatase, BDP (BCKDH phosphatase), which causes activation. In the present study, the effect of the disruption of the BDK gene on growth and development of mice was investigated. BCKDH activity was much greater in most tissues of BDK\u2212\/\u2212 mice. This occurred in part because the E1 component of the complex cannot be phosphorylated due to the absence of BDK and also because greater than normal amounts of the E1 component were present in tissues of BDK\u2212\/\u2212 mice. Lack of control of BCKDH activity resulted in markedly lower blood and tissue levels of the BCAAs in BDK\u2212\/\u2212 mice. At 12\u00a0weeks of age, BDK\u2212\/\u2212 mice were 15% smaller than wild-type mice and their fur lacked normal lustre. Brain, muscle and adipose tissue weights were reduced, whereas weights of the liver and kidney were greater. Neurological abnormalities were apparent by hind limb flexion throughout life and epileptic seizures after 6\u20137 months of age. Inhibition of protein synthesis in the brain due to hyperphosphorylation of eIF2\u03b1 (eukaryotic translation initiation factor 2\u03b1) might contribute to the neurological abnormalities seen in BDK\u2212\/\u2212 mice. BDK\u2212\/\u2212 mice show significant improvement in growth and appearance when fed a high protein diet, suggesting that higher amounts of dietary BCAA can partially compensate for increased oxidation in BDK\u2212\/\u2212 mice. Disruption of the BDK gene establishes that regulation of BCKDH by phosphorylation is critically important for the regulation of oxidative disposal of BCAAs. The phenotype of the BDK\u2212\/\u2212 mice demonstrates the importance of tight regulation of oxidative disposal of BCAAs for normal growth and neurological function.<\/jats:p>","DOI":"10.1042\/bj20060869","type":"journal-article","created":{"date-parts":[[2006,10,27]],"date-time":"2006-10-27T13:04:55Z","timestamp":1161954295000},"page":"153-162","update-policy":"https:\/\/doi.org\/10.1042\/crossmark_policy","source":"Crossref","is-referenced-by-count":113,"title":["Impaired growth and neurological abnormalities in branched-chain \u03b1-keto acid dehydrogenase kinase-deficient mice"],"prefix":"10.1042","volume":"400","author":[{"given":"Mandar\u00a0A.","family":"Joshi","sequence":"first","affiliation":[{"name":"Department of Biochemistry and Molecular Biology, Indiana University School of Medicine, Indianapolis, IN 46202, U.S.A."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Nam\u00a0Ho","family":"Jeoung","sequence":"additional","affiliation":[{"name":"Department of Biochemistry and Molecular Biology, Indiana University School of Medicine, Indianapolis, IN 46202, U.S.A."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mariko","family":"Obayashi","sequence":"additional","affiliation":[{"name":"Department of Biochemistry and Molecular Biology, Indiana University School of Medicine, Indianapolis, IN 46202, U.S.A."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Eyas\u00a0M.","family":"Hattab","sequence":"additional","affiliation":[{"name":"Department of Pathology and Laboratory Medicine, Indiana University School of Medicine, Indianapolis, IN 46202, U.S.A."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Eric\u00a0G.","family":"Brocken","sequence":"additional","affiliation":[{"name":"Department of Pathology and Laboratory Medicine, Indiana University School of Medicine, Indianapolis, IN 46202, U.S.A."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Edward\u00a0A.","family":"Liechty","sequence":"additional","affiliation":[{"name":"Department of Pediatrics, Indiana University School of Medicine, Indianapolis, IN 46202, U.S.A."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Michael\u00a0J.","family":"Kubek","sequence":"additional","affiliation":[{"name":"Department of Anatomy and Cell Biology, Indiana University School of Medicine, Indianapolis, IN 46202, U.S.A."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Krishna\u00a0M.","family":"Vattem","sequence":"additional","affiliation":[{"name":"Department of Biochemistry and Molecular Biology, Indiana University School of Medicine, Indianapolis, IN 46202, U.S.A."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ronald\u00a0C.","family":"Wek","sequence":"additional","affiliation":[{"name":"Department of Biochemistry and Molecular Biology, Indiana University School of Medicine, Indianapolis, IN 46202, U.S.A."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Robert\u00a0A.","family":"Harris","sequence":"additional","affiliation":[{"name":"Department of Biochemistry and Molecular Biology, Indiana University School of Medicine, Indianapolis, IN 46202, U.S.A."}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"288","published-online":{"date-parts":[[2006,10,27]]},"reference":[{"key":"2021112217501997200_B1","doi-asserted-by":"crossref","first-page":"39","DOI":"10.1097\/00075197-200401000-00008","article-title":"Molecular mechanisms through which amino acids mediate signaling through the mammalian target of rapamycin","volume":"7","author":"Kimball","year":"2004","journal-title":"Curr. 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