Small-molecule inhibitor: ebelactone A

Name

History: Ebelactones A and B, natural products from Streptomyces aburaviensis, were described by Umezawa et al. (1980) as esterase inhibitors.
Peptidases inhibited: Carboxypeptidase Y (Majima et al., 1999). Serine carboxypeptidase A, often termed "urinary kininase" or "carboxypeptidase Y-like kininase" in this literature (Ito et al., 1999). Acylaminoacyl peptidase (Scaloni et al., 1992). Non-peptidase hydrolases that are inhibited include cutinases and lipases produced by fungal plant pathogens (Koller et al., 1990; Voigt et al., 2005), pancreatic lipase (Nonaka et al., 1996) and isoprenylated cysteine methyl ester hydrolase (Tan & Rando, 1992).
Mechanism: Inhibition is presumably irreversible, due to covalent modification of the catalytic Ser. Satoh et al. (2004) found that ebelactone B exhibited a mixed non-competitive inhibitory effect and was selective for carboxypeptidase Y over serine carboxypeptidase A and serine carboxypeptidase D.
Pharmaceutical relevance: Serine carboxypeptidase A, as urinary carboxypeptidase, contributes to the catabolism of bradykinin on the luminal side of the renal tubules, and its inhibition by ebelactone reduces high blood in some model systems (Nakajima et al., 2000).

CID at PubChem: 6436820
Structure
Chemical/biochemical name: (3S,4S)-4-[(E,2S,6R,8S,9R,10R)-9-hydroxy-4,6,8,10-tetramethyl-7-oxo-dodec-4-en-2-yl]-3-methyl-oxetan-2-one
Formula weight: 338

Comment: The molecule of ebelactone B differs from that of ebelactone A simply in the addition of a methylene group (see Structure). The enzymes inhibited by the ebelactones are all serine peptidases in clan SC, or non-peptidase homologues of them, but they have varied substrate specificities.