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4185443
Mito be more than a power house: structural and functional analysis of the human mitochondrial acyl carrier protein (mACP) and ketosynthase (OXSM)
Date
March 27, 2025
Outside of their involvement in energy production, mitochondria play a critical role in cells through their access to a discrete fatty acid biosynthetic pathway. While human mitochondria import some fatty acids from the cytoplasm for energy production through β-oxidation, its fatty acid synthase (FAS) pathway is considered the sole system for producing fatty acid moieties within mitochondria for lipoic acid synthesis and membrane lipid modification. Despite decades of study in bacterial FASs (the putative evolutionary mitochondrial precursor), our understanding of human mitochondrial fatty acid biosynthesis remains incomplete. In our studies, we established a robust and scalable method for the recombinant expression and purification of mACP, ensuring access to the protein for activity and biophysical studies. The elemental behaviors of mACP, substrate sequestration and chain flipping, were explored using solvatochromism, an environmentally sensitive fluoresce. This provides an efficient approach toward understanding the fundamental protein−protein interactions (PPIs) of mACP and its partner proteins. Furthermore, by leveraging the mechanism-based crosslinking probes developed in our lab, we successfully conducted structural biological studies to analyze the structures and the essential PPIs between mACP and its partner protein 3-oxoacyl-ACP synthase (OXSM) via x-ray crystallography for the very first time. Understanding these interactions may offer insights into genetic mitochondrial diseases implicating FAS, ultimately assisting therapeutic development.
Fatty acids are prevalent in all walks of life and are produced by fatty acid synthases (FASs) in which an acyl carrier protein (ACP) tethers a growing acyl chain as it is elongated and modified by a series of partner proteins…
Carrier protein-dependent biosynthetic pathways produce a diverse range of primary and secondary metabolites, many of which manifest in our daily lives as therapeutics and antibiotics…
_Mycobacterium tuberculosis_ (Mtb) is a global leading cause of death, with an increasing occurrence of drug-resistant infections due to the production of mycolic acids derived from type II fatty acid biosynthesis (FAS-II) that are incorporated into the cell wall…
Nonribosomal peptides (NRPs) are a large class of secondary metabolites which have found extensive use as therapeutics including cyclosporine, daptomycin, and vancomycin…