Small-molecule inhibitor: chymostatin

Summary Structure Literature

Name

Common name
chymostatin

Inhibition

History
Chymostatin was described as an inhibitor of chymotrypsin by Umezawa et al. (1970).
Peptidases inhibited
Numerous peptidases have been reported to be inhibited, mainly serine peptidases from families S1 and S8, and cysteine peptidases from family C1. Other peptidases inhibited include signal peptide peptidase A: Ichihara et al., 1984), the chymotrypsin-like activity of the eukaryotic proteasome: Djaballah et al., 1992) and the archaean proteasome: Ditzel et al., 1997). Most of the susceptible peptidases are endopeptidases able to accommodate a hydrophobic residue in the S1 subsite.
Mechanism
The aldehyde function of the inhibitor forms a hemiacetal or thiohemiacetal with the catalytic serine, cysteine or threonine of the peptidase (Delbaere & Brayer, 1985; Bullock et al., 1996).
DrugBank
DB01683

Chemistry

CID at PubChem
443119
ChEBI
510447
Structure
[chymostatin (S01.001 inhibitor) structure ]
Chemical/biochemical name
N-[(S)-1-carboxy-2-phenylethyl]-carbamoyl-alpha-N-[2-iminohexahydro-4(S)-pyrimidyl]-S-glycyl-L-leucyl-phenylalaninal
Formula weight
608

General

Inhibitor class
This is a compound of the aldehyde class. The discovery of leupeptin in the late 1960s drew attention to the potential of aldehydes as peptidase inhibitors, and the inhibition of papain by synthetic aldehydes was further studied by Wolfenden and co-workers (e.g. Westerik & Wolfenden, 1972). Many aldehydes are now known as inhibitors of serine, cysteine or threonine peptidases. They form hemiacetal or thiohemiacetal conjugates with the essential hydroxyl or thiol group of the enzyme that are transition state analogues (Bendall et al., 1977). The compounds exist predominantly in their hydrated forms in aqueous solution, but only the aldehyde is an effective inhibitor (Bendall et al., 1977). Peptide aldehydes and semicarbazones are valuable ligands for affinity chromatography of serine and cysteine peptidases (Rich et al., 1986; Dando & Barrett, 1992). Aldehydes can also act as inhibitors of metallopeptidases (Strater & Lipscomb, 1995).
Comment
The 1-carboxy-2-phenylethyl]-carbamoyl group is present also in antipain. The unusual amino acid, [2-iminohexahydro-4(S)-pyrimidyl]-(S)-glycine, is found also in elastatinal.