Understanding the Structure and Function of Type I Acyl Carrier Protein and its Interaction with Growing Acyl Chain

Abstract

Fatty acids are central to the formation of biological membranes and play important roles in metabolism. There are two major classes of fatty acid synthases (FAS); Type I present in mammals and yeast that utilizes large multifunctional enzyme complexes, while type II, harbored by prokaryotes and plants, utilizing discrete monofunctional enzymes. Acyl Carrier Protein (ACP) is a universal and highly conserved player in both the pathways. ACP is modified from apo to holo form by enzyme 4′‐Phosphopantetheinyl Transferase (PPT). PPT enzyme is crucial for growth of many pathogens and is therefore regarded as a potential drug target. Structural and biochemical studies on type II ACP highlight various aspects of ACP‐PPT and ACP‐acyl chain interaction. However, acyl chain binding and dynamic interactions of type I ACP are not well understood. We therefore intend to understand the function of type I ACP, their interaction with bound acyl chain and cognate and non cognate transferases. Literature highlights the importance of type I FAS in the survival and pathogenicity of fungal pathogens like C. albicans and C. parasilopsis. For our studies, we employed type I ACP from Saccharomyces cereviceae and its putative PPT enzyme. Using NMR spectroscopy we show that the growing acyl chain was sequestered up to a certain carbon chain length in the hydrophobic core of the protein employing a unique motif. In conclusion, our studies provide some interesting insights into the structure and function of type I ACP and the molecular mechanism it employs to protect the growing acyl chain. Our findings can provide new avenues for structure based drug designing.Support or Funding InformationDepartment of Biotechnology, India