Crystal structure and catalytic activity of the <scp>PPM</scp>1K N94K mutant

Dolatabad, Meisam Rostaminasab; Guo, Lulu; Peng, Xiao; Zhu, Zhongliang; He, Qing-Tao; Du, Yang; Qu, Changxiu; Guo, Shengchao; Xiaolei, Fu; Li, Rui-rui; Ge, Lin; Hu, Kejia; Liu, Hongda; Shen, Yue; Yu, Xiao; Sun, Junying; Zhang, Pengju

doi:10.1111/jnc.14631

Cited by 8 publications

(3 citation statements)

References 46 publications

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“…PP2Cm is a BCKDH phosphatase encoded by the PPM1K gene and is highly conserved in vertebrates ( Lu et al, 2009 ; Dolatabad et al, 2019 ). The phosphatase activity of PP2Cm is dependent on Mn 2+ bound in the active site ( Wynn et al, 2012 ).…”

Section: Bckdh Regulation In Skeletal Musclementioning

confidence: 99%

Branched-chain Amino Acids: Catabolism in Skeletal Muscle and Implications for Muscle and Whole-body Metabolism

et al. 2021

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Branched-chain amino acids (BCAAs) are critical for skeletal muscle and whole-body anabolism and energy homeostasis. They also serve as signaling molecules, for example, being able to activate mammalian/mechanistic target of rapamycin complex 1 (mTORC1). This has implication for macronutrient metabolism. However, elevated circulating levels of BCAAs and of their ketoacids as well as impaired catabolism of these amino acids (AAs) are implicated in the development of insulin resistance and its sequelae, including type 2 diabetes, cardiovascular disease, and of some cancers, although other studies indicate supplements of these AAs may help in the management of some chronic diseases. Here, we first reviewed the catabolism of these AAs especially in skeletal muscle as this tissue contributes the most to whole body disposal of the BCAA. We then reviewed emerging mechanisms of control of enzymes involved in regulating BCAA catabolism. Such mechanisms include regulation of their abundance by microRNA and by post translational modifications such as phosphorylation, acetylation, and ubiquitination. We also reviewed implications of impaired metabolism of BCAA for muscle and whole-body metabolism. We comment on outstanding questions in the regulation of catabolism of these AAs, including regulation of the abundance and post-transcriptional/post-translational modification of enzymes that regulate BCAA catabolism, as well the impact of circadian rhythm, age and mTORC1 on these enzymes. Answers to such questions may facilitate emergence of treatment/management options that can help patients suffering from chronic diseases linked to impaired metabolism of the BCAAs.

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Section: Bckdh Regulation In Skeletal Musclementioning

confidence: 99%

Branched-chain Amino Acids: Catabolism in Skeletal Muscle and Implications for Muscle and Whole-body Metabolism

et al. 2021

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“…The relationship between Mg content and MSUD could be explained from recent reports that have stated that Mg is a core element of phosphatase Mg 2+ /Mn 2+ -dependent 1K (PPM1K), which is an important metabolic regulator associated with MSUD and with type 2 diabetes, as well as with other cardiovascular and neurological diseases. 23 …”

Section: Resultsmentioning

confidence: 99%

Trace elements in dried blood spots as potential discriminating features for metabolic disorder diagnosis in newborns

et al. 2021

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Trace elements in dried blood spots (DBSs) from newborns were determined by laser ablation coupled with inductively coupled plasma mass spectrometry, and data were subjected to chemometric evaluation in an attempt to classify healthy newborns and newborns suffering from metabolic disorders. Unsupervised [principal component analysis (PCA) and cluster analysis (CA)] and supervised [linear discriminant analysis (LDA) and soft independent modeling by class analogy (SIMCA)] pattern recognition techniques were used as classification techniques. PCA and CA have shown a clear tendency to form two groups (healthy newborns and newborns suffering from metabolic disorders). LDA and SIMCA have predicted that 90.5% and 83.9% of originally grouped healthy newborn cases were correctly classified by LDA and SIMCA, respectively. In addition, these percentages were 97.6% (LDA) and 80.6% (SIMCA) for DBSs from newborns suffering from metabolic disorders. However, SIMCA has only detected one misclassified DBS from the healthy group, and the lower percentage is attributed to four DBSs from the healthy newborn group and five DBSs from newborns with disorders that were found as belonging to both categories (healthy newborns and newborns with disorders) in the training set. LDA also gave a percentage of grouped maple syrup urine disease (MSUD) cases correctly classified of 100%, although the percentage fells to 66.7% when classifying phenylketonuria (PKU) cases. Finally, essential elements such as Fe, K, Rb, and Zn were found to be matched (correlated) with the concentration of amino acids such as phenylalanine, valine, and leucine, biomarkers linked with MSUD and PKU diseases.

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“…A mutant PPM1K protein with an S248A mutation was resistant to the effects of MPCi on PhosTAG™ gel mobility, suggesting that this could be an important site of covalent modification in response to MPCi. Though the functional effects of this modification remain to be determined, work on the crystal structure of PPM1K suggests that serine 248 is localized near the active site cleft of PPM1K (42), which could affect the intrinsic phosphatase activity of this enzyme. Available data indicate an increase in PPM1K serine 248 phosphorylation in 10-week-old ob/ob mice, as well as acute downregulation of this phosphosite in after refeeding fasted mice (34) (mitomod.biochem.wisc.edu).…”

Section: Discussionmentioning

confidence: 99%

Mitochondrial Pyruvate Carrier Inhibition Initiates Metabolic Crosstalk to Stimulate Branched Chain Amino Acid Catabolism

Ferguson

Eichler

Yiew

et al. 2022

Preprint

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The mitochondrial pyruvate carrier (MPC) has emerged as a therapeutic target for treating insulin resistance, type 2 diabetes, and nonalcoholic steatohepatitis (NASH). We evaluated whether MPC inhibitors (MPCi) might correct impairments in branched chain amino acid (BCAA) catabolism, which are predictive of developing diabetes and NASH. In a randomized, placebo-controlled trial of an MPCi (MSDC-0602K) in people with NASH (EMMINENCE; NCT02784444), MSDC-0602K treatment, which led to marked improvements in insulin sensitivity and diabetes, decreased plasma concentrations of BCAAs compared to baseline while placebo had no effect. The rate-limiting enzyme in BCAA catabolism is the mitochondrial branched chain ketoacid dehydrogenase (BCKDH), which is deactivated by phosphorylation. BCKDH phosphorylation was reduced in liver of obese, hepatocyte-specific MPC2 knockout (LS-Mpc2-/-) mice compared to wild-type controls. In multiple human hepatoma cell lines, MPCi markedly reduced BCKDH phosphorylation and stimulated branched chain keto acid catabolism. Mechanistically, the effects of MPCi could be mimicked by activating mitochondrial pyruvate oxidation and reversed by addition of mitochondrial-permeable methyl-pyruvate, suggesting that intramitochondrial pyruvate accumulation suppresses BCKDH activity. The effects of MPCi on BCKDH phosphorylation were mediated by the BCKDH phosphatase PPM1K, and MPCi treatment also reduced phosphorylation of PPM1K likely at a key serine residue near the substrate binding cleft. These data demonstrate novel cross talk between mitochondrial pyruvate and BCAA metabolism and suggest that MPC inhibition leads to lower plasma BCAA concentrations and BCKDH phosphorylation via the phosphatase PPM1K.

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Crystal structure and catalytic activity of the PPM1K N94K mutant

Cited by 8 publications

References 46 publications

Branched-chain Amino Acids: Catabolism in Skeletal Muscle and Implications for Muscle and Whole-body Metabolism

Branched-chain Amino Acids: Catabolism in Skeletal Muscle and Implications for Muscle and Whole-body Metabolism

Trace elements in dried blood spots as potential discriminating features for metabolic disorder diagnosis in newborns

Mitochondrial Pyruvate Carrier Inhibition Initiates Metabolic Crosstalk to Stimulate Branched Chain Amino Acid Catabolism

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