Research
Molybdenum cofactor (Moco) is a redox enzyme cofactor and used by a variety of enzymes that are involved purine and sulfur catabolism in humans and anaerobic respiration in bacteria. Moco and Moco-dependent enzymes are essential for survival or adaptation in most organisms. Genetic mutations or pharmacological inhibition can result in the inability to biosynthesize Moco, causing severe effects on the physiology of organisms. For instance, human Moco biosynthesis is crucial for brain development, and malfunction of enzymes in Moco synthesis causes Moco deficiency (MoCD) diseases, a fatal metabolic disorder. On the other hand, inhibition of bacterial Moco biosynthesis has been shown to reduce virulence.
Purpose
The overall goal of studying the catalytic mechanism of MoaC is to understand the importance of this enzyme in pathogens. To aid this work, our laboratory recently developed a MoaC irreversible inhibitor, the uncleavable substrate analog (3',8-cH2GMP[CH2]PP; Our preliminary Mass Spectroscopy (MS) analysis suggests that treatment of E. coli MoaC with 3',8-cH2GMP[CH2]PP yields a modification of 503 Da ( putative Compound Y). Based on the crystal structure of MoaC in complex with its native substrate, 3'8-cH2GTP, or with the product, cPMP, and with guiding mechanistic considerations, I hypothesize that (1) the covalent modification of MoaC takes place on one of the six catalytic amino acid residues and (2) the structure of the covalently modified MoaC will help guide future inhibitor development to target multiple pathogens.
Publications
Di Li, Kenichi Yokoyama, Maria A. Schumacher. Unlocking Mysteries of MoaC: The power of covalent linkage. (Manuscript in preparation)
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Duc Huynh, Kalina Tsolova, Abigail Watson, Sai Kwan Khal, Jordan Green, Di Li, Jimin Hu, Erik Soderblom, Jen-Tsan Chi, Chantell Evans. O-GlcNAcylation regulates neurofilament-light assembly and function and is perturbed by Charcot-Marie-Tooth disease mutations. Nat Commun. 2023 Sep 19. https://doi.org/10.1038/s41467-023-42227-0. (Published research paper)
Di Li, Haoran Pang, Quinglin Wu, Alexey Silakov, Pei Zhou, Kenichi Yokoyama. Mechanism of regulation of radical initiation in MoaA radical SAM GTP 3’,8- cyclase. (Manuscript prepared for submission)
Kenichi Yokoyama, Di Li, Haoran Pang. Resolving the Multidecade-Long Mystery in MoaA Radical SAM Enzyme Reveals New
Opportunities to Tackle Human Health Problems. ACS Bio & Med Chem Au. 2021 Dec 13. doi: 10.1021/acsbiomedchemau.1c00046. (Published review paper)
Andrey S. Krasilnikov, Di Li, Hyunwook Lee, Carol Bator, Igor Berezin, Susan Hafenstein, Anna Perederina. Cryo-EM structure of catalytic ribonucleoprotein complex RNase MRP. Nat Commun. 2020 July 10. doi:10.1038/s41467-020-17308-z. (Published research paper)
Yue Wang, Xiaorui Li, Jiahao Zhang, Qiang Liu, Peng Gao, Di Li, Shijie Zhang, Ju Liu. CIZ1 Expression Is Upregulated in Hemangioma of the Tongue. Pathol Oncol Res. 2018 Nov 19. doi: 10.1007/s12253-018-0495-4. (Published research paper)