Small-molecule inhibitor: tyrostatin

Name

History: Tyrostatin was isolated from the actinomycete bacterium Kitasatosporia sp. 55 by Oda et al. (1989).
Peptidases inhibited: Tyrostatin is a potent inhibitor of sedolisin and sedolisin-B, but not of kumamolisin) or kumamolisin-As (Wlodawer et al., 2004). The structure of tyrostatin is very similar to that of tyropeptin A (N-isovaleryl-tyrosyl-valyl-tyrosinal) from another species of Kitasatosporia; tyropeptin A inhibits some activities of the proteasome (XT01-001), so cross-inhibition is to be expected.
Mechanism: Inhibition is reversible. K_i = 2.6 nM for sedolisin (Oda et al., 1992).

Structure
Chemical/biochemical name: N-isovaleryl-tyrosyl-leucyl-tyrosinal
Related inhibitors: pseudo-tyrostatin; iodotyrostatin; pseudo-iodotyrostatin; tyropeptin A

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: Pseudo-tyrostatin is N-isovaleryl-tyrosyl-tyrosinal (Wlodawer et al., 2004).
Reviews: Wlodawer et al. (2004)