METABOLISM-COUPLED PROTEIN POST-TRANSLATIONAL MODIFICATIONS IN C. ELEGANS AND MAMMALIAN MODELS

The regulation of cellular processes is governed by intricate biochemical mechanisms, which often rely on metabolic feedback on protein function, for example, by way of product inhibition of enzymes and protein post-translational modifications (PTMs). PTMs are chemical modifications that occur on proteins after their synthesis, enabling rapid and often reversible functional responses to cellular and environmental changes. Most of the hundreds of known PTMs are derived from small molecule metabolites, with continued characterization efforts of the metabolome and PTMs deepening our understanding of related biological regulatory mechanisms that impact health and disease. This dissertation delves broadly into the coupling between metabolism and PTMs, exploring both the upstream metabolic events contributing to and the downstream pathways influenced by PTM dynamics.The first chapter, a review focusing primarily on recent examples from the past 3–4 years, demonstrates how the availability of a broad range of metabolites tightly controls functionally important PTMs. It emphasizes the chemical diversity of PTMs, the compartment-specific roles of metabolic enzymes in PTM occurrence, and the necessity of untargeted mass spectrometry-based approaches to uncover new PTM-involved regulatory mechanisms. The second chapter describes discovery of a family of conserved metabolites, N-acylspermidines, which were uncovered from mass feature-level untargeted comparative metabolomic analyses of wildtype Caenorhabditis elegans (C. elegans) and a knock-out mutant of the mitochondrial sirtuin sir-2.3. N-acylspermidines were found to be downstream of mitochondrial sirtuin function and have negative impacts on C. elegans lifespan and cancer cell proliferation. The third chapter focuses on protein fatty acylation in C. elegans, revealing distinct fatty acylation patterns at both amino acid type and protein levels. The monomethyl branched-chain 15-methylhexadecanoylation was found to be the most abundant cysteine fatty acylation. Using its clickable alkyne analog and other straight chain alkyne fatty acids, the author developed the first comprehensive fatty acylated proteome database for C. elegans. The fourth chapter introduces a novel PTM, the conjugation between lysine residue and electrophilic metabolite propionaldehyde, termed ‘C3-iminylation’. The protein-modifying propionaldehyde was found to be derived from cytochrome P450-mediated oxidation of omega-3 fatty acids, an essential nutrient of significant interest.

Name thesis:degree_name

Ph. D., Chemistry and Chemical Biology

Level thesis:degree_level

Doctor of Philosophy

Discipline thesis:degree_discipline

Chemistry and Chemical Biology

Grantor

Cornell University

Year dc:date.issued

2024

Author dc:creator

• Zhang, Bingsen

Committee members dc:contributor.committeemember

• Lin, Hening
• Cerione, Richard

• fatty acylation
• metabolism
• omega 3
• post-translational modification
• sirtuin
• spermidine

Language dc:language.iso

en

DOI

http://doi.org/10.7298/gfxy-g526

Dc Identifier Other

ProQuest Submission ID: 14676
ProQuest Publication ID: 31564222

OAI identifier oai:identifier

oai:ecommons.cornell.edu:1813/117235