Small-molecule inhibitor: ubiquitin aldehyde

Name

History: Pickart & Rose (1986) found that a ubiquitin-C-terminal hydrolase was inactivated by borohydride in the presence of ubiquitin, and that this was due to the generation of ubiquitin aldehyde by reduction at the C-terminus. Ubiquitin aldehyde inhibited the ubiquitinyl-hydrolase by the formation of an extremely tight complex in which the inhibitor was presumabed to be bound to the active site in a manner analogous to the tetrahedral intermediate of catalysis. It was proposed that ubiquitin aldehyde is a general inhibitor of ubiquitin-recycling processes (Hershko & Rose, 1987).
Peptidases inhibited: Peptidases inhibited include ubiquitin-specific cysteine peptidases in families C12 and C19. SARS coronavirus 3C-like peptidase is also reported to be inhibited (Ratia et al., 2006). Adenain, otubain-1 and otubain-2 have affinity for ubiquitin aldehyde, and can be presumed to be inhibited (Balakirev et al., 2002; Balakirev et al., 2003). We are aware of few reports of cysteine peptidases not being inhibited by ubiquitin aldehyde, so the degree of selectivity of the reagent is uncertain.
Mechanism: Inhibition is reversible. Kinetics of inhibition have been investigated by Melandri et al. (1996), and crystal structures of ubiquitin aldehyde in complex with target enzymes have been reported by Johnston et al. (1999), Hu et al. (2002) and Hu et al. (2005).

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: Ubiquitin aldehyde, containing 76 amino acids, is not strictly a small-molecule inhibitor, but it is placed here because it is synthetic, and especially because, being an aldehyde, its mechanism of inhibition is comparable to that of many small-molecule inhibitors of protein-nucleophile peptidases.