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Acyl carrier proteins (ACPs) are involved in primary and secondary metabolic pathways, including the fatty acid biosynthesis that is required for all domains of life. This single protein must deliver pathway intermediates to the appropriate enzyme, distinguishing between a multitude of possible intermediate-enzyme combinations. The intermediate is delivered to the active site of enzymes through a large conformational change termed “chain flipping.” Whether chain flipping is a stochastic or regulated process has remained a mystery. We have combined the techniques of probe development, protein NMR, molecular dynamic simulations, and protein-protein docking simulations to decipher the rules associated with metabolite identity and enzyme activity in ACP dependent pathways. This study provides the first clear evidence for an allosteric regulation mechanism in any ACP dependent pathway, demonstrating that when the substrate interacts with the interior helical bundle, it confers structural changes to the exterior, which are recognized by enzymes via protein-protein interactions; presenting a new paradigm for understanding these biosynthetic pathways.
In the current study of polyketide and non-ribosomal peptide biosynthesis, a major goal has been the structural elucidation of the megasynthases that produce them. We have been developing chemical biology tools to study these enzyme systems, with a focus on dual site-selective crosslinking probes…
We have developed a new strategy to identify natural product biosynthetic pathways from complex microbial ecosystems that combines chemical biology tools with single cell sequencing…
_Mycobacterium tuberculosis_ (MTB) is the pathogen that causes tuberculosis (TB), a global epidemic and a leading cause of death worldwide, killing more people annually than HIV/AIDS…
_Mycobacterium tuberculosis_ (Mtb) is the causative agent of the disease, tuberculosis (TB), and a leading cause of death worldwide. The pathogenicity of tuberculosis infections is largely due to the unique cell wall structure of the bacteria, which contains mycolic acids…