A bioorthogonal chemical reporter for fatty acid synthase-dependent protein acylation

Abstract

Cells acquire fatty acids from dietary sources or via de novo palmitate production by fatty acid synthase (FASN). Although most cells express FASN at low levels, it is upregulated in cancers and during replication of many viruses. The precise role of FASN in disease pathogenesis is poorly understood, and whether de novo fatty acid synthesis contributes to host or viral protein acylation has been traditionally difficult to study. We describe a cell permeable, click-chemistry compatible alkynyl-acetate analog (Alk-4) that functions as a reporter of FASN-dependent protein acylation. In a FASN-dependent manner, Alk-4 selectively labeled the cellular protein interferon-induced transmembrane protein 3 (IFITM3) at its palmitoylation sites, and the HIV-1 matrix protein at its myristoylation site. Alk-4 metabolic labeling also enabled biotin-based purification and identification of more than 200 FASN-dependent acylated cellular proteins. Thus, Alk-4 is a useful bioorthogonal tool to selectively probe FASN-mediated protein acylation in normal and diseased states.

Fatty Acid Synthase inhibitor TVB-3166 prevents S-acylation of the Spike protein of human coronaviruses

“…6C), suggests that the FASN is also critical to generating the CoA species used for these reactions. In support of this notion, two recent studies have found that FASN generates an array of fatty acyl chains than just 16:0 and that FASN supports the generation of myristoyl-CoA and stearoyl-CoA and their subsequent attachment to proteins (61,62). Does the loss of ZDHHC5 and FASN activity impact the SARS-CoV2 infection cycle by other mechanisms?…”

FASN inhibitor TVB-3166 prevents S-acylation of the spike protein of human coronaviruses

“…5 D), suggests that the FASN is also critical to generating the CoA species used for these reactions. In support of this notion, two recent studies have found that FASN generates an array of fatty acyl chains beyond just 16:0 and that FASN supports the generation of myristoyl-CoA and stearoyl-CoA and their subsequent attachment to proteins ( 68 , 69 ).…”