期刊
JOURNAL OF CLINICAL INVESTIGATION
卷 119, 期 6, 页码 1678-1687出版社
AMER SOC CLINICAL INVESTIGATION INC
DOI: 10.1172/JCI38151
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资金
- NCRR NIH HHS [RR 022371, S10 RR022371] Funding Source: Medline
- NHLBI NIH HHS [HL70079, R21 HL096041, P01 HL080111, HL080111, R01 HL087132, HL62311, R01 HL077440, R01 HL088975, R01 HL062311, R01 HL070079, HL087132] Funding Source: Medline
- NIDDK NIH HHS [DK053843, R01 DK062880-07, R01 DK062880-06, R01 DK062880, DK062880, R01 DK053843] Funding Source: Medline
- PHS HHS [HLP01-008111] Funding Source: Medline
The branched-chain amino acids (BCAA) are essential amino acids required for protein homeostasis, energy balance, and nutrient signaling. In individuals with deficiencies in BCAA, these amino acids can be preserved through inhibition of the branched-chain-alpha-ketoacid dehydrogenase (BCKD) complex, the rate-limiting step in their metabolism. BCKD is inhibited by phosphorylation of its E1 alpha subunit at Ser293, which is catalyzed by BCKD kinase. During BCAA excess, phosphorylated Ser293 (pSer293) becomes dephosphorylated through the concerted inhibition of BCKD kinase and the activity of an unknown intramitochondrial phosphatase. Using unbiased, proteomic approaches, we have found that a mitochondrial-targeted phosphatase, PP2Cm, specifically binds the BCKD complex and induces dephosphorylation of Ser293 in the presence of BCKD substrates. Loss of PP2Cm completely abolished substrate-induced Ela dephosphorylation both in vitro and in vivo. PP2Cm-deficient mice exhibited BCAA catabolic defects and a metabolic phenotype similar to the intermittent or intermediate types of human maple syrup urine disease (MSUD), a hereditary disorder caused by defects in BCKD activity. These results indicate that PP2Cm is the endogenous BCKD phosphatase required for nutrient-mediated regulation of BCKD activity and suggest that defects in PP2Cm may be responsible for a subset of human MSUD.
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