Synthetic protein lipidation

•Diversity and dynamics of protein fatty acyl modifications in signal transduction.•Roles of protein fatty acylation in apoptosis, cancer and neurodegeneration.•Synthetic molecules for probing protein fatty acylation.•Inhibitors of fatty acyl transferases and protein fatty acylation. Fatty acylation of proteins is a versatile co-translational or post-translational modification that plays a key role in human physiology and disease. It is tightly controlled by a set of enzymes which catalyze the covalent attachment of fatty acids onto protein substrates, resulting in regulation of protein function, stability and interaction with other proteins or membranes. Some fatty acyltransferases have emerged to function as tumor suppressors or oncogenes, while others contribute to pathogenesis and neurodegenerative disorders. Yet our understanding of the molecular mechanism of action of these enzymes and their substrate selectivity is still in its infancy. The use of synthetic chemistry combined with state-of-the-art techniques in cell biology is enabling systematic investigation of protein fatty acylation and its dynamics. This review highlights synthetic probes for detecting and modulating protein fatty acylation, such as palmitoylation and myristoylation, and it provides an outlook on the potential influence chemical biology can have in shaping the future of the field of protein fatty acylation.