4BMK

Serine Palmitoyltransferase K265A from S. paucimobilis with bound PLP- Myriocin Aldimine

Summary for 4BMK

• Entry DOI: 10.2210/pdb4bmk/pdb
• Descriptor: SERINE PALMITOYLTRANSFERASE, PYRIDOXAL-5'-PHOSPHATE, Decarboxylated Myriocin, ... (5 entities in total)
• Functional Keywords: transferase-antibiotic complex, transferase, external aldimine, inhibitor, sphingolipids, natural product, antibiotic isp-1, transferase/antibiotic
• Biological source: SPHINGOMONAS PAUCIMOBILIS
• Total number of polymer chains: 2
• Total formula weight: 96081.49

Authors

Wadsworth, J.M.,Clarke, D.J.,McMahon, S.A.,Beattie, A.E.,Lowther, J.,Dunn, T.M.,Naismith, J.H.,Campopiano, D.J. (deposition date: 2013-05-09, release date: 2013-09-04, Last modification date: 2023-12-20)

Primary citation

Wadsworth, J.M.,Clarke, D.J.,Mcmahon, S.A.,Lowther, J.P.,Beattie, A.E.,Langridge-Smith, P.R.R.,Broughton, H.B.,Dunn, T.M.,Naismith, J.H.,Campopiano, D.J.
The Chemical Basis of Serine Palmitoyltransferase Inhibition by Myriocin.
J.Am.Chem.Soc., 135:14276-, 2013

PubMed Abstract: 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.

PubMed: 23957439
DOI: 10.1021/JA4059876

Experimental method

X-RAY DIFFRACTION (1.62 Å)