The chemical basis of serine palmitoyltransferase inhibition by myriocin

J Am Chem Soc. 2013 Sep 25;135(38):14276-85. doi: 10.1021/ja4059876. Epub 2013 Sep 11.


Sphingolipids (SLs) are essential components of cellular membranes formed from the condensation of L-serine and a long-chain acyl thioester. This first step is catalyzed by the pyridoxal-5'-phosphate (PLP)-dependent enzyme serine palmitoyltransferase (SPT) which is a promising therapeutic target. The fungal natural product myriocin is a potent inhibitor of SPT and is widely used to block SL biosynthesis despite a lack of a detailed understanding of its molecular mechanism. By combining spectroscopy, mass spectrometry, X-ray crystallography, and kinetics, we have characterized the molecular details of SPT inhibition by myriocin. Myriocin initially forms an external aldimine with PLP at the active site, and a structure of the resulting co-complex explains its nanomolar affinity for the enzyme. This co-complex then catalytically degrades via an unexpected 'retro-aldol-like' cleavage mechanism to a C18 aldehyde which in turn acts as a suicide inhibitor of SPT by covalent modification of the essential catalytic lysine. This surprising dual mechanism of inhibition rationalizes the extraordinary potency and longevity of myriocin inhibition.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Crystallography, X-Ray
  • Fatty Acids, Monounsaturated / chemistry*
  • Kinetics
  • Mutation
  • Recombinant Proteins / chemistry
  • Serine C-Palmitoyltransferase / antagonists & inhibitors*
  • Serine C-Palmitoyltransferase / chemistry
  • Serine C-Palmitoyltransferase / genetics
  • Sphingomonas / enzymology
  • Sphingomonas / genetics


  • Fatty Acids, Monounsaturated
  • Recombinant Proteins
  • Serine C-Palmitoyltransferase
  • thermozymocidin

Associated data

  • PDB/4BMK