Skip to Main Content
 

Global Search Box

 
 
 

ETD Abstract Container

Abstract Header

Molecular Mechanism and Metabolic Function of the S-nitroso-coenzyme A Reductase AKR1A1

Stomberski, Colin Thomas
http://orcid.org/0000-0002-3362-9345
http://rave.ohiolink.edu/etdc/view?acc_num=case1554372852266484

Abstract Details

2019, Doctor of Philosophy, Case Western Reserve University, Biochemistry.
The majority of nitric oxide’s (NO) biological effect across cell types and tissues occurs through protein S-nitrosylation, the oxidative, posttranslational modification of cysteine thiols in proteins by NO to form S-nitrosothiols (SNOs). Through S-nitrosylation, NO controls protein activity, stability, interactions with other proteins, and subcellular localization to alter cellular function. NO also modifies small molecule thiols, primarily glutathione and coenzyme A, to serve as SNO-based signaling molecules. S-nitroso-glutathione (GSNO) and S-nitroso-coenzyme A (SNO-CoA) signal through S-nitrosylation of target proteins and are regulated by enzymatic denitrosylases, proteins that metabolize GSNO and SNO-CoA. SNO-CoA was recently identified as a conserved metabolic signal transducer regulated by the activity of S-nitroso-coenzyme A reductases (SCoRs). The discovery of SNO-CoA generates numerous, fundamental questions regarding how SNOs derive specificity in signaling, how enzymes recognize different SNOs, and endogenous roles of SNO-CoA in mammals. This thesis addresses these questions by providing a mechanistic understanding of how aldo-keto reductase 1A1 (AKR1A1), the mammalian SCoR, specifically recognizes SNO-CoA among myriad S-nitrosothiols, identifying targets of SCoR-dependent denitrosylation in mammalian cells and tissues, and exploring metabolic processes regulated by the SCoR/SNO-CoA system of S-nitrosylation and denitrosylation. Here we use a combination of in silico molecular modeling, in vitro biochemical assays, cell culture models, and animal models to address these questions. We find that SCoR binds SNO-CoA through both the CoA moiety and NO group; the latter finding provides the first evidence of direct SNO recognition by enzymes and explains how SCoR can identify SNO-CoA among the multitude of SNOs and CoA derivatives. SCoR also controls the S-nitrosylation of metabolic proteins and alters mitochondrial metabolism. Finally, SCoR regulates mammalian cholesterol metabolism by modulating the S-nitrosylation and secretion of the hypercholesterolemic risk factor gene proprotein convertase subtilisin/kexin type 9 (PCSK9) to increase low-density lipoprotein receptor (LDLR) stability and lower serum cholesterol, providing a fundamental mechanism by which nitric oxide controls cholesterol homeostasis. Remarkably, chemical inhibition of SCoR in mice lowers serum cholesterol levels. Overall, the work presented herein investigates SCoR from basic understanding of the structure—function relationship of the enzyme to potential translational application of targeting SCoR in hypercholesterolemia.
Jonathan Stamler (Advisor)
Focco van den Akker (Committee Chair)
Mukesh Jain (Committee Member)
George Dubyak (Committee Member)
Hung-Ying Kao (Committee Member)
192 p.
Biochemistry
AKR1A1; SNO-CoA; S-nitroso-coenzyme A; S-nitroso-coenzyme A reductase; SNO-CoA reductase

Recommended Citations

Citations

  • Stomberski, C. T. (2019). Molecular Mechanism and Metabolic Function of the S-nitroso-coenzyme A Reductase AKR1A1 [Doctoral dissertation, Case Western Reserve University]. OhioLINK Electronic Theses and Dissertations Center. http://rave.ohiolink.edu/etdc/view?acc_num=case1554372852266484

    APA Style (7th edition)

  • Stomberski, Colin. Molecular Mechanism and Metabolic Function of the S-nitroso-coenzyme A Reductase AKR1A1. 2019. Case Western Reserve University, Doctoral dissertation. OhioLINK Electronic Theses and Dissertations Center, http://rave.ohiolink.edu/etdc/view?acc_num=case1554372852266484.

    MLA Style (8th edition)

  • Stomberski, Colin. "Molecular Mechanism and Metabolic Function of the S-nitroso-coenzyme A Reductase AKR1A1." Doctoral dissertation, Case Western Reserve University, 2019. http://rave.ohiolink.edu/etdc/view?acc_num=case1554372852266484

    Chicago Manual of Style (17th edition)

case1554372852266484
467
© 2019, all rights reserved.
This open access ETD is published by Case Western Reserve University School of Graduate Studies and OhioLINK.
Release 3.2.12