E-64 is an

epoxide In organic chemistry, an epoxide is a cyclic ether () with a three-atom ring. This ring approximates an equilateral triangle, which makes it strained, and hence highly reactive, more so than other ethers. They are produced on a large scale ...

which can irreversibly inhibit a wide range of cysteine peptidases. The compound was first isolated and identified from ''

Aspergillus japonicus ''Aspergillus violaceofuscus'' is a species of fungus in the genus ''Aspergillus''. It belongs to the group of black Aspergilli which are important industrial workhorses. ''A. violaceofuscus'' belongs to the ''Nigri'' section. The species was fir ...

'' in 1978. It has since been shown to inhibit many cysteine peptidases such as papain,

cathepsin B Cathepsin B belongs to a family of lysosomal cysteine proteases known as the cysteine cathepsins and plays an important role in intracellular proteolysis. In humans, cathepsin B is encoded by the ''CTSB'' gene. Cathepsin B is upregulated in ce ...

, cathepsin L,

calpain A calpain (; , ) is a protein belonging to the family of calcium-dependent, non-lysosomal cysteine proteases ( proteolytic enzymes) expressed ubiquitously in mammals and many other organisms. Calpains constitute the C2 family of protease clan C ...

and staphopain. The low toxic effects of the inhibitor, in addition to its effective mechanism of action, makes E-64 a potential template for drugs to treat diseases where high levels of a

cysteine protease Cysteine proteases, also known as thiol proteases, are hydrolase enzymes that degrade proteins. These proteases share a common catalytic mechanism that involves a nucleophilic cysteine thiol in a catalytic triad or dyad. Discovered by Gopal Ch ...

s are the primary cause.

Structure and mechanism of inhibition

E-64 possesses a ''trans''-epoxysuccinic acid group coupled to a modified

dipeptide A dipeptide is an organic compound derived from two amino acids. The constituent amino acids can be the same or different. When different, two isomers of the dipeptide are possible, depending on the sequence. Several dipeptides are physiologicall ...

. The covalent attachment of E-64 to the active site cysteine occurs via nucleophillic attack from the

thiol In organic chemistry, a thiol (; ), or thiol derivative, is any organosulfur compound of the form , where R represents an alkyl or other organic substituent. The functional group itself is referred to as either a thiol group or a sulfhydryl gro ...

group of the cysteine on C2 of the epoxide. Early studies suggested that the amino-4-guanidinobutane bound in the S3' subsite and the leucyl group in the S2' subsite, however published crystal structures of E-64 complexed with papain indicated that E-64 binds via the S subsites.

References

{{reflist Epoxides Guanidines Protease inhibitors Carboxylic acids Carboxamides Dipeptides

Structure and mechanism of inhibition

See also

References