Chuang (David) Lab

David Chuang Lab's research focuses on the biochemistry and structural biology of macromolecular machines.

The Chuang Lab focuses on the structure/function and clinical ramifications of the pyruvate dehydrogenase (PDC) complex and the branched-chain α-ketoacid dehydrogenase (BCKDC) complex and their corresponding regulatory enzymes, i.e. the specific kinases and phosphatases. PDC and BCKDC are highly related mitochondrial protein machines that control the oxidation of glucose and branched-chain amino acids (BCAA), respectively, the latter as a group comprising leucine, isoleucine, and valine. Both glucose and BCAA levels are elevated in obesity, type 2 diabetes, heart failure, and cancer. Recently, we employed high-throughput screening and structure-based design to develop a new generation of small-molecule inhibitors against pyruvate dehydrogenase kinase isoforms 1-4 (PDKs 1-4) and the single BCKD kinase (BDK). These specific kinase inhibitors are capable of augmenting glucose and branched-chain amino acid (BCAA) fluxes and show promise in restoring glucose and BCAA homeostasis in rodent models for diabetes/metabolic syndrome and heart failure.

Meet the Team

David Chuang, Ph.D.

David Chuang, Ph.D.

Principal Investigator

Professor
Department of Biochemistry

Richard (Max) Wynn, Ph.D.

Richard (Max) Wynn, Ph.D.

Associate Professor
Department of Internal Medicine

Featured Publications

  1. Sharma, G., Wu. C. Y., Wynn, R. M., Gui, W., Malloy, C. R., Sherry, A. D., Chuang, D. T., Khemtong, C.. (2019) Real-time hyperpolarized 13C magnetic resonance detects increased pyruvate oxidation in pyruvate dehydrogenase kinase 2/4-double knockout mouse livers. Sci Rep. 9:16480. PMID: 31712597
  2. Chen, M., Gao, C., Yu, J., Ren, S., Wang, M., Wynn, R. M., Chuang, D. T., Wang, Y., Sun, H. (2019) Therapeutic Effect of Targeting Branched-Chain Amino Acid Catabolic Flux in Pressure-Overload Induced Heart Failure. J Am Heart Assoc. 8: e011625. PMID: 31433721
  3. Zhou, M., Shao, J., Wu, C. Y., Shu, L., Dong, W., Liu, Y., Chen, M., Wynn, R. M., Wang, J., Wang, J., Gui, W. J., Qi, X., Lusis, A. J., Li, Z., Wang, W., Ning, G., Yang, X., Chuang, D. T., Wang, Y., Sun, H. (2019) Targeting BCAA Catabolism to Treat Obesity-Associated Insulin Resistance. Diabetes. 68: 1730-1746. PMID: 3116787
  4. White, P. J., McGarrah, R. W., Grimsrud, A., Tso, S-C, Yang, W.-H., Haldeman, J., Grenier-Larouche, T., An, J., Lapworth, A. L., Astapova, I., Hannou, S. A., George, T., Arlotto, M., Olson, L. B., Lai, M., Zhang, G., Ilkayeva, O., Thompson, J. W., Herman, M. A., Wynn, R. M., Chuang, D. T., Newgard, C. B. The BCKDH kinase and phosphatase integrate BCAA and lipid metabolism via regulation of ATP-citrate lyase. Cell Metabolism. (2018) 27, 1281-1293. PMCID: PMC5990471
  5. Wu, C. Y., Tso, S.-C., Chuang, J. L., Gui, W. J., Lou, M., Sharma, G., Khemtong, C., Qi, X., Wynn, R. M., Chuang, D. T. Targeting hepatic pyruvate dehydrogenase kinases restores insulin signaling and mitigates ChREBP-mediated lipogenesis in diet-induced obese mice. Mol Metab. (2018) Jun;12:12-24. PMID: 29656110.
  6. Wu C-Y, Satapati S, Gui W, Wynn RM, Sharma G, Lou M, Qi X, Burgess SC, Malloy C, Khemtong C, Sherry AD, Chuang DT, Merritt ME. A Novel Inhibitor of Pyruvate Dehydrogenase Kinase Stimulates Myocardial Carbohydrate Oxidation in Diet-Induced Obesity. J. Biol. Chem. (2018) 293(25):9604-9613. PMCID: 29739849.
  7. Sun, H., Olson, K. C., Gao, C., Prosdocimo, D. A., Zhou, M., Wang, Z., Jeyaraj, D., Youn, J. Y., Ren, S., Liu, Y., Rau, C. D., Shah, S., Ilkayeva, O., Gui, W.-J., William, N.S., Wynn, R. M., Newgard, C. B., Cai, H., Xiao, X., Chuang, D. T., Schulze, P. C., Lynch, C., Jain, M. K., and Wang, Y. (2016). Catabolic Defect of Branched-Chain Amino Acids Promotes Heart Failure. 133: 2038-2049.
  8. Tso, S.-C., Gui, W.J., Wu, C.-Y, Chuang, J. L., Qi, X., Skvorak, K. J., Dorko, K., Wallace, A. L., Morlock, L. K., Lee, B. H., Hutson, S. M., Strom, S. C., Williams, N. S., Tambar, U. K., Wynn, R. M., Chuang, D. T. (2014). Benzothiophene carboxylate derivatives as novel allosteric inhibitors of branched-chain α-ketoacid dehydrogenase kinase. J. Biol. Chem. 289: 20583-20593. PMID 24895126
  9. Tso, S.-C., Qi, X, Gui, W. J, Wu, C.-Y., Chuang, J. L., Wernstedt-Asterholm, I., Morlock, L. K., Owens, K. R., Scherer, P. E., Williams, N. S., Tambar, U. K., Wynn, R. M. and Chuang, D. T. (2014). Structure-guided development of specific pyruvate dehydrogenase kinase inhibitors targeting the ATP-binding pocket. Biol. Chem. 289: 4432-4443. PMID: 24356970
  10. Tso, S.-C., Qi, X., Gui, W.-J., Chuang, J. L., Morlock, L. K., Wallace, A. L., Ahmed, K., Laxman, S., Campeau, P. M., Lee, B. H., Hutson, S. M., Tu, B. P., Williams, N. S., Tambar, U. K., Wynn, R. M., and Chuang, D. T. (2013). Structure-based design and mechanisms of allosteric inhibitors for mitochondrial branched-chain α-ketoacid dehydrogenase kinase. Natl. Acad. Sci. U. S. A. 110: 9728-9733. PMID: 23716694
  11. Kennerson, L., Yiu, E. M., Chuang, D. T., Kidambi, A., Tso, S.-C., Ly, C., Chaudhry, R., Drew, A. P., Rance, G., Delatycki, M.,  Zuchner, S., Monique, M., Ryan, M. M., Garth A., and Nicholson, G. A. (2013). A New Locus for X-linked Dominant Charcot Marie Tooth Disease (CMTX6) is Caused by Mutations in the Pyruvate Dehydrogenase Kinase Isoenzyme 3 (PDK3) Gene. Hum. Mol. Genet. 22: 1404-1416.
  12. Brunetti-Pierri, N., Lanpher, B., Erez, A., Ananieva, E. A., Islam, M., Marini, J. C., Sun, Q., Yu, C., Hegde, M., Li, J., Wynn, R. M., Chuang, D. T., Hutson, S., and Lee, B. (2011). Phenylbutyrate therapy for maple syrup urine disease. Mol. Genet20: 631-640.
  13. Wynn, R. M., Kato, M., Chuang, J. L., Tso, S.-C., Li, J., and Chuang, D. T. (2008). Pyruvate dehydrogenase kinase-4 structures reveal a metastable open conformation fostering robust core-free basal activity. J. Biol. Chem. 283: 25305-25315.
  14. Kato, M., Wynn, R. M., Chuang, J. L., Tso, S.-C., Machius, M., Li, J., and Chuang, D. T. (2008). Structural basis for inactivation of the human pyruvate dehydrogenase complex by phosphorylation; Role of disordered phosphorylation loops. Structure 16: 1849-1859.
  15. Ludtke, S. J., Baker, M. L., Chen, D.-H., Song, J.-L. Chuang, D. T., and Chiu, W. (2008). De novo backbone trace of GroEL from single particle electron cryo-microscopy. Structure 16: 441-448.
  16. Kato, M., Wynn, R. M., Chuang, J. L., Brautigam, C. A., Custorio, M., and Chuang, T. (2006). A synchronized substrate-gating mechanism revealed by cubic-core structure of the bovine branched-chain α-ketoacid dehydrogenase complex. EMBO J. 25: 5983-5994.
  17. Kato, M., Chuang, J. L., Tso, S.-C., Wynn, R.M., and Chuang, D. T. (2005). Crystal structure of pyruvate dehydrogenase kinase 3 bound to lipoyl domain 2 of the human pyruvate dehydrogenase complex. EMBO J. 24: 1763-1774.
  18. Brautigam, C. A., Chuang, J. L., Tomchick, D. R., Machius, M. and Chuang, D. T. (2005). Crystal structure of human dihydrolipoamide dehydrogenase: NAD+/NADH binding and the structural basis of disease-causing mutations. Mol. Biol. 350:543-552.
  19. Wynn, R. M., Kato, M., Machius, M., Chuang J. L., Li J, Tomchick D. R., and Chuang, D. T. (2004). Molecular mechanism for regulation of the human mitochondrial branched-chain α-ketoacid dehydrogenase complex by phosphorylation. Structure 12: 2185-2196.
  20. Machius, M., Chuang, J. L., Wynn, R. M., Tomchick, D. R., and Chuang, D. T. (2001). Structure of rat BCKD kinase: Nucleotide-induced domain communication in a mitochondrial protein kinase. Natl. Acad. Sci. U.S.A. 98: 11218-23. PMCID: PMC58710
  21. Song, J.-L., Wynn. R. M., and Chuang, D. T. (2000). Interactions of GroEL/GroES with a heterodimeric intermediate during α2β2 assembly of mitochondrial branched-chain α-ketoacid dehydrogenase. Cis capping of the native-like 86-kDa intermediate by GroES. Biol. Chem. 275: 22305-22312.
  22. Ævarsson, A., Chuang, J. L., Wynn, R. M., Turley, S., Chuang, D. T., and Hol, W. G. H. (2000). Crystal structure of human branched-chain α-ketoacid dehydrogenase and molecular basis of multienzyme complex deficiency in maple syrup urine disease. Structure 8: 277-291. PMID: 10745006

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Dallas, TX 75390-9038
Office: L4.260A

 

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