The structure and function of the cell membrane, as well as many aspects of energy metabolism and cell cycling, are directly dependent on acyl-CoA thioesters and their CoA and fatty acid constituents. The complex interplay between CoA, short or long chain carboxylates, and acyl-CoA thioesters (and lipid derived products) in directing the functions and responses of cells is not well understood even at the most elementary level. This research program focuses on the delineation of cellular processes in which transformations of acyl-CoA metabolites or acyl-S-proteins play important roles. The catalysts for these transformations reside mainly in the hotdog fold superfamily. An integrated approach that combines the efforts of a diverse research team will be used to characterize hotdog thioesterases at the cellular, chemical, mechanistic, and structural levels. The overall goal is to gain an understanding of the relationships that exist between enzyme structures and the mechanisms of substrate recognition and catalysis in vitro and in vivo. This fundamental knowledge is required for the development of new drugs and for the discovery of new biochemical processes. An understanding of the relationship between in vitro chemical function (i.e., range of substrates and catalytic efficiencies) and the actual cellular chemical function (i.e., physiological substrates and in vivo catalytic efficiencies) will provide insight into the need for and mechanism of regulation of thioesterase activity within the cell. In addition, knowledge about relationships between structure and chemical and cellular functions should reveal how thioesterases successfully execute their evolved biological roles.

Public Health Relevance

This project employs an integrated approach that relies on a multidisciplinary research team to define the hotdog thioesterases at the cellular, chemical, mechanistic, and structural levels. The results of this effort will facilitate the development of new therapeutic drugs and the discovery of new biochemical processes.

Agency
National Institute of Health (NIH)
Institute
National Institute of General Medical Sciences (NIGMS)
Type
Research Project (R01)
Project #
5R01GM028688-29
Application #
8080168
Study Section
Macromolecular Structure and Function E Study Section (MSFE)
Program Officer
Barski, Oleg
Project Start
1996-02-01
Project End
2013-06-30
Budget Start
2011-07-01
Budget End
2013-06-30
Support Year
29
Fiscal Year
2011
Total Cost
$485,998
Indirect Cost
Name
University of New Mexico
Department
Chemistry
Type
Schools of Arts and Sciences
DUNS #
868853094
City
Albuquerque
State
NM
Country
United States
Zip Code
87131
Latham, John A; Ji, Tianyang; Matthews, Kaila et al. (2017) Catalytic Mechanism of the Hotdog-Fold Thioesterase PA1618 Revealed by X-ray Structure Determination of a Substrate-Bound Oxygen Ester Analogue Complex. Chembiochem 18:1935-1943
Wu, Rui; Latham, John A; Chen, Danqi et al. (2014) Structure and catalysis in the Escherichia coli hotdog-fold thioesterase paralogs YdiI and YbdB. Biochemistry 53:4788-805
Latham, John A; Chen, Danqi; Allen, Karen N et al. (2014) Divergence of substrate specificity and function in the Escherichia coli hotdog-fold thioesterase paralogs YdiI and YbdB. Biochemistry 53:4775-87
Wang, Min; Song, Feng; Wu, Rui et al. (2013) Co-evolution of HAD phosphatase and hotdog-fold thioesterase domain function in the menaquinone-pathway fusion proteins BF1314 and PG1653. FEBS Lett 587:2851-9
Chen, Danqi; Latham, John; Zhao, Hong et al. (2012) Human brown fat inducible thioesterase variant 2 cellular localization and catalytic function. Biochemistry 51:6990-9
Zhuang, Zhihao; Latham, John; Song, Feng et al. (2012) Investigation of the catalytic mechanism of the hotdog-fold enzyme superfamily Pseudomonas sp. strain CBS3 4-hydroxybenzoyl-CoA thioesterase. Biochemistry 51:786-94
Song, Feng; Thoden, James B; Zhuang, Zhihao et al. (2012) The catalytic mechanism of the hotdog-fold enzyme superfamily 4-hydroxybenzoyl-CoA thioesterase from Arthrobacter sp. strain SU. Biochemistry 51:7000-16
Zhao, Hong; Lim, Kap; Choudry, Anthony et al. (2012) Correlation of structure and function in the human hotdog-fold enzyme hTHEM4. Biochemistry 51:6490-2
Kim, Alexander; Benning, Matthew M; OkLee, Sang et al. (2011) Divergence of chemical function in the alkaline phosphatase superfamily: structure and mechanism of the P-C bond cleaving enzyme phosphonoacetate hydrolase. Biochemistry 50:3481-94
Li, Zhimin; Kulakova, Liudmila; Li, Ling et al. (2009) Mechanisms of catalysis and inhibition operative in the arginine deiminase from the human pathogen Giardia lamblia. Bioorg Chem 37:149-61

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