This is a competitive renewal of R01 GM086703. Nicotinamide adenine dinucleotide (NAD), commonly known as an important redox cofactor in biology, are also used as a co-substrate by many NAD-consuming enzymes. These enzymes include CD38 (an NAD glycohydrolase and cyclase), poly(ADP-ribose) polymerases (PARPs), and sirtuins (NAD-dependent protein lysine deacylases). All these NAD-consuming enzymes have important biological functions and deregulation of them is associated with various human diseases, including cancer, diabetes, and neurodegeneration. However, many fundamental questions about the functions of NAD-consuming enzymes are poorly understood. The goal of this proposal is to develop and use chemical probes to help understand the function of these NAD consuming enzymes. In the last four years with NIH support, we have developed several NAD analogs to study these NAD- consuming enzymes and have made a number of important progresses. These include the development of covalent cell permeable probes for CD38, the development of a clickable NAD analog for labeling the substrate proteins of PARPs, and the discovery of Sirt5 as an NAD-dependent desuccinylase/demalonylase and Sirt6 as an NAD-dependent defatty-acylase. Building on these progresses, in this proposal, we will use the probes we already developed to understand the function of CD38 and PARPs, and to develop new probes for the study of PARPs and sirtuins. We believe our proposed studies will provide important insights to understand the biological functions of NAD-consuming enzymes, lead to the discovery of novel protein posttranslational modifications, and ultimately lead to the development of better therapeutics for treating human diseases involving NAD-consuming enzymes.

Public Health Relevance

This proposal aims to study NAD-consuming enzymes using synthetic NAD analogs. The proposed studies will lead to better understandings of these enzymes, the discovery of new protein posttranslational modifications, and ultimately new treatment options for several human diseases including cancer.

Agency
National Institute of Health (NIH)
Institute
National Institute of General Medical Sciences (NIGMS)
Type
Research Project (R01)
Project #
2R01GM086703-06
Application #
8631881
Study Section
Synthetic and Biological Chemistry A Study Section (SBCA)
Program Officer
Fabian, Miles
Project Start
2008-12-01
Project End
2018-07-31
Budget Start
2014-09-10
Budget End
2015-07-31
Support Year
6
Fiscal Year
2014
Total Cost
$269,199
Indirect Cost
$94,199
Name
Cornell University
Department
Chemistry
Type
Schools of Arts and Sciences
DUNS #
872612445
City
Ithaca
State
NY
Country
United States
Zip Code
14850
Tong, Zhen; Wang, Yi; Zhang, Xiaoyu et al. (2016) SIRT7 Is Activated by DNA and Deacetylates Histone H3 in the Chromatin Context. ACS Chem Biol 11:742-7
Chiang, Ying-Ling; Lin, Hening (2016) An improved fluorogenic assay for SIRT1, SIRT2, and SIRT3. Org Biomol Chem 14:2186-90
Bheda, Poonam; Jing, Hui; Wolberger, Cynthia et al. (2016) The Substrate Specificity of Sirtuins. Annu Rev Biochem 85:405-29
Gibson, Bryan A; Zhang, Yajie; Jiang, Hong et al. (2016) Chemical genetic discovery of PARP targets reveals a role for PARP-1 in transcription elongation. Science 353:45-50
Jiang, Hong; Zhang, Xiaoyu; Lin, Hening (2016) Lysine fatty acylation promotes lysosomal targeting of TNF-α. Sci Rep 6:24371
Jing, Hui; Lin, Hening (2015) Sirtuins in epigenetic regulation. Chem Rev 115:2350-75
Shrimp, Jonathan H; Hu, Jing; Dong, Min et al. (2014) Revealing CD38 cellular localization using a cell permeable, mechanism-based fluorescent small-molecule probe. J Am Chem Soc 136:5656-63
Jiang, Hong; Khan, Saba; Wang, Yi et al. (2013) SIRT6 regulates TNF-* secretion through hydrolysis of long-chain fatty acyl lysine. Nature 496:110-3
Jiang, Hong; Sherwood, Robert; Zhang, Sheng et al. (2013) Identification of ADP-ribosylation sites of CD38 mutants by precursor ion scanning mass spectrometry. Anal Biochem 433:218-26
Hu, Jing; He, Bin; Bhargava, Shiva et al. (2013) A fluorogenic assay for screening Sirt6 modulators. Org Biomol Chem 11:5213-6

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