The chemical basis of serine palmitoyltransferase inhibition by myriocin.
J Am Chem Soc
; 135(38): 14276-85, 2013 Sep 25.
Article
in En
| MEDLINE
| ID: mdl-23957439
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.
Full text:
1
Collection:
01-internacional
Database:
MEDLINE
Main subject:
Fatty Acids, Monounsaturated
/
Serine C-Palmitoyltransferase
Language:
En
Journal:
J Am Chem Soc
Year:
2013
Document type:
Article
Affiliation country:
United kingdom