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A Chemoproteomic Atlas of the Human Purine Interactome for Regioselective Ligand Discovery

ABSTRACT: Purines are essential bioactive molecules that interact with a large fraction of the human proteome. Despite their importance, the scope of actionable purine-binding pockets for ligand discovery remains limited. Here, we developed a quantitative chemoproteomics platform using sulfonyl-purine (SuPUR) chemistry to produce a massive and functional map of the human purine interactome. The SuPUR platform captured 31,000+ targetable tyrosine and lysine sites, representing the most comprehensive beyond cysteine chemoproteomics database for enabling protein ligand discovery. SuPUR ligands that bind through a regioselective fashion serve as enabling starting points for developing potent (nanomolar) and proteome-wide-selective modulators of enzymatic and protein-protein interaction function. Phenotypic screening identified a site-specific (Y237) and regioselective SuPUR ligand of ACAT2 to reveal an unexpected metabolic dependency in cancer cells. A crystal structure of SuPUR ligand-bound ACAT2 revealed the purine group binds deep in the CoA pocket forming key interactions with catalytic residues via a water bridge to guide future structure-based ligand design.

INSTRUMENT(S):

ORGANISM(S): Homo Sapiens (human)

TISSUE(S): Squamous Epithelial Cell, Embryonic Stem Cell

DISEASE(S): Prostate Adenocarcinoma

SUBMITTER: Ku-Lung Hsu

LAB HEAD: Ku-Lung Hsu

PROVIDER: PXD075707 | Pride | 2026-03-29

REPOSITORIES: Pride

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			Action	DRS
	20240216_BoDo_MLH01_LF_ZH_3_015_MEM_FP_4f.raw	Raw
	20240216_BoDo_MLH01_LF_ZH_3_015_SOL_FP_4f.raw	Raw
	20240216_BoDo_MLH01_LF_ZH_3_021_MEM_ABHD10_FP_4f.raw	Raw
	20240216_BoDo_MLH01_LF_ZH_3_021_MEM_ABHD10_REP2_FP_4f.raw	Raw
	20240216_BoDo_MLH01_LF_ZH_3_021_SOL_ABHD10_FP_4f.raw	Raw

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A Chemoproteomic Atlas of the Human Purine Interactome for Regioselective Ligand Discovery

Project description:Purines are essential bioactive molecules that interact with a large fraction of the human proteome. Despite their importance, the scope of actionable purine-binding pockets for ligand discovery remains limited. Here, we developed a quantitative chemoproteomics platform using sulfonyl-purine (SuPUR) chemistry to produce a massive and functional map of the human purine interactome. The SuPUR platform captured 31,000+ targetable tyrosine and lysine sites, representing the most comprehensive beyond cysteine chemoproteomics database for enabling protein ligand discovery. SuPUR ligands that bind through a regioselective fashion serve as enabling starting points for developing potent (nanomolar) and proteome-wide-selective modulators of enzymatic and protein-protein interaction function. Phenotypic screening identified a site-specific (Y237) and regioselective SuPUR ligand of ACAT2 to reveal an unexpected metabolic dependency in cancer cells. A crystal structure of SuPUR ligand-bound ACAT2 revealed the purine group binds deep in the CoA pocket forming key interactions with catalytic residues via a water bridge to guide future structure-based ligand design

2026-03-29 | PXD071955 | Pride

ASB11 controls purinosome formation through PAICS ubiquitination

Project description:Purine act as building block for DNA and RNA, provide cellular energy and signaling, and can generate cofactors such as NADH and coenzyme A. Purine de novo synthesis pathway begins with amino acids, ribose 5-phosphate, CO2 and NH3 with 6 enzymes and 10 enzymatic steps to convert PRPP to IMP. In previous study, under purine-depleted or other stimuli the six enzymes will form dynamic and reversible complex called purinosome to enhance the pathway flux. However, the mechanism of purinosome formation is unknown. Phosphoribosyl aminoimidazole succinocarboxamide synthetase (PAICS), an enzyme involved in the step7 and 8 of purine biosynthesis. In our lab, we used interactome and ubiquiylome to identify PAICS, which is a substrate of ASB11. ASB11 is a substrate adaptor of cullin 5 ubiquitin ligase complex and is able to bind PAICS for ubiquitination. Here, we found that ASB11 could increase purinosome formation without any stimuli. This effect depends on ASB11 E3 function, which can ubiquitinate PAICS on K74 site. We generate K74R mutation of PAICS so that ASB11 couldn’t ubiquitinate it. Interestingly, this mutant reduces the formation of purinosomes under purine-depleted and other stressed conditions. After further research, we found ASB11 expression level will increase under some specific conditions. Moreover, we analyzed TCGA database and found that the expression of ASB11 in melanoma cell is higher than normal cell. Consistent with our finding, melanoma cell has partially formed purinosome under basal condition because of the higher expression of ASB11. We guess that ASB11 may plays an important role in cancer cell.

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Project description:Folate metabolism is intricately linked to purine de novo synthesis through the incorporation of folate-derived one-carbon units into the purine scaffold. Here, we investigate the chemical and genetic dependencies caused by mutations in the folate enzyme MTHFD1 and discover a key role for Nudix hydrolase 5 (NUDT5) in regulating purine de novo synthesis. Through genetic knockout and development of a selective chemical NUDT5 degrader, we uncover an unprecedented scaffolding role rather than NUDT5 enzymatic activity is responsible for this phenotype. We find that NUDT5 interacts with the rate-limiting enzyme of purine de novo synthesis, PPAT, to repress the pathway in response to elevated purine levels. Our findings establish NUDT5 as an important regulator of purine de novo synthesis and elucidate its role in mediating sensitivities to purine analogs in cancer treatment and to adenosine in MTHFD1 deficiency.

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