Small Molecule Inhibition of CPS1 Activity through an Allosteric Pocket

Yao, Shihua; Nguyen, Tuong-Vi; Rolfe, Alan; Agrawal, Anant A.; Ke, Jiyuan; Peng, Shouyong; Colombo, Federico; Yu, Sean; Bouchard, Patricia; Wu, Jiayi; Huang, Kuan-Chun; Bao, Xingfeng; Omoto, Kiyoyuki; Selvaraj, Anand; Yu, Lihua; Ioannidis, Stephanos; Vaillancourt, Frédéric H.; Zhu, Ping; Larsen, Nicholas; Bolduc, David M.

doi:10.1016/j.chembiol.2020.01.009

Cited by 24 publications

(36 citation statements)

References 46 publications

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“…To further examine whether OD alleviated APAP hepatotoxicity in a urea cycle-dependent manner, we used H3B-120 (a potent Cps1 inhibitor) to inhibit the urea cycle [ 22 ]. Mice were pretreated with H3B-120 (20 mg/kg) 12 h before APAP administration.…”

Section: Resultsmentioning

confidence: 99%

Oridonin Alters Hepatic Urea Cycle via Gut Microbiota and Protects against Acetaminophen-Induced Liver Injury

Hong

Liu

Chen

et al. 2021

Oxidative Medicine and Cellular Longevity

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Acetaminophen (APAP) hepatotoxicity is the leading cause of acute liver failure in the western world. Oridonin (OD), which is the major active ingredient of the traditional Chinese medicine Rabdosia rubescens, reportedly exerts anti-inflammatory and antioxidative effects. Here, we first find that OD protects against APAP-induced hepatotoxicity. The results of hepatic tissue-associated RNA-seq and metabolomics showed that the protective effects of OD were dependent upon urea cycle regulation. And such regulation of OD is gut microbiota partly dependent, as demonstrated by fecal microbiota transplantation (FMT). Furthermore, using 16S rRNA sequencing, we determined that OD significantly enriched intestinal Bacteroides vulgatus, which activated the nuclear factor erythroid 2-related factor 2 (Nrf2) pathway to regulate redox homeostasis against APAP by urea cycle. In conclusion, our study suggests that the Bacteroides vulgatus-urea cycle-Nrf2 axis may be a potential target for reducing APAP-induced liver injury, which is altered by OD.

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Section: Resultsmentioning

confidence: 99%

Oridonin Alters Hepatic Urea Cycle via Gut Microbiota and Protects against Acetaminophen-Induced Liver Injury

Hong

Liu

Chen

et al. 2021

Oxidative Medicine and Cellular Longevity

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“…Removal of succinyl and glutaryl groups from lysine residues of CPS1 and OTC by SIRT5 (Du et al, 2011) could be a protective mechanism that ensures efficient ureagenesis, since SIRT5 deficient mice experience hyperammonemia (Nakagawa et al, 2009). Recently, the three-dimensional structure 6UEL of human CPS1 liganded with an inhibitor intended for treatment of cancers became available (Yao et al, 2020). So, we used the 6UEL structure to repeat our analysis (Supplementary Figure S1).…”

Section: Comparative Analysis Of Cps1 and Otc Surface Residues Whose Mutations Disrupt Ureagenesis And Cause Diseasementioning

confidence: 99%

“…The M729, S1203, and D1205 are mutated in patients with CPS1 deficiency, and their relative SASA is greater than 25% in the 6UEL structure. However, the biological significance of this result is unclear since 6UEL structure represents inactive form of CPS1 liganded with the H3B-193 inhibitor of CPS1 enzymatic activity (Yao et al, 2020). Therefore, solvent exposure of the M792, S1203, and D1205 residues in the 6UEL structure could well be a result of an inactive conformation induced by the CPS1 inhibitor.…”

Section: Comparative Analysis Of Cps1 and Otc Surface Residues Whose Mutations Disrupt Ureagenesis And Cause Diseasementioning

confidence: 99%

Mitochondrial Enzymes of the Urea Cycle Cluster at the Inner Mitochondrial Membrane

et al. 2021

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Mitochondrial enzymes involved in energy transformation are organized into multiprotein complexes that channel the reaction intermediates for efficient ATP production. Three of the mammalian urea cycle enzymes: N-acetylglutamate synthase (NAGS), carbamylphosphate synthetase 1 (CPS1), and ornithine transcarbamylase (OTC) reside in the mitochondria. Urea cycle is required to convert ammonia into urea and protect the brain from ammonia toxicity. Urea cycle intermediates are tightly channeled in and out of mitochondria, indicating that efficient activity of these enzymes relies upon their coordinated interaction with each other, perhaps in a cluster. This view is supported by mutations in surface residues of the urea cycle proteins that impair ureagenesis in the patients, but do not affect protein stability or catalytic activity. We find the NAGS, CPS1, and OTC proteins in liver mitochondria can associate with the inner mitochondrial membrane (IMM) and can be co-immunoprecipitated. Our in-silico analysis of vertebrate NAGS proteins, the least abundant of the urea cycle enzymes, identified a protein-protein interaction region present only in the mammalian NAGS protein—“variable segment,” which mediates the interaction of NAGS with CPS1. Use of super resolution microscopy showed that NAGS, CPS1 and OTC are organized into clusters in the hepatocyte mitochondria. These results indicate that mitochondrial urea cycle proteins cluster, instead of functioning either independently or in a rigid multienzyme complex.

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“…In this issue, Yao and colleagues (Yao et al, 2020) developed an enzymatic assay to evaluate ADP production by CPS1, as CPS1 consumes two ATP molecules to convert ammonia to carbamoyl phosphate through multistep reactions. Using this assay, the authors performed high-throughput screening of chemical libraries containing approximately 350,000 compounds to identify candidate inhibitors of CPS1, which led to the identification of the H3B-120 compound.…”

mentioning

confidence: 99%

“…Pegylated arginine deiminase (ADI-PEG20), a bioengineered enzyme that degrades arginine into citrulline and ammonia, has shown promising results in early clinical trials for some solid tumors (Keshet et al, 2018;Martinez-Outschoorn et al, 2017). The small molecule CPS1 inhibitor developed by Yao et al (2020) will provide a useful tool to further investigate CPS1-related metabolic vulnerabilities and prospects for CPS1-targeting cancer therapy.…”

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confidence: 99%

A Promising CPS1 Inhibitor Keeping Ammonia from Fueling Cancer

Taguchi

Fahrmann

Hanash

2020

Cell Chemical Biology

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Small Molecule Inhibition of CPS1 Activity through an Allosteric Pocket

Abstract: Highlights d A high-throughput screen identifies a small-molecule inhibitor of CPS1, H3B-120 d H3B-120 binds to an allosteric pocket to achieve highly selective inhibition of CPS1 d Analogs of H3B-120 block CPS1 cellular activity in primary human hepatocytes

Cited by 24 publications

References 46 publications

Oridonin Alters Hepatic Urea Cycle via Gut Microbiota and Protects against Acetaminophen-Induced Liver Injury

Oridonin Alters Hepatic Urea Cycle via Gut Microbiota and Protects against Acetaminophen-Induced Liver Injury

Mitochondrial Enzymes of the Urea Cycle Cluster at the Inner Mitochondrial Membrane

A Promising CPS1 Inhibitor Keeping Ammonia from Fueling Cancer

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