Irreversible inhibition of papain by epoxysuccinyl peptides.  Carbon-13 NMR characterization of the site of alkylation

Yabe, Yuichiro; Guillaume, Dominique; Rich, Daniel H.

doi:10.1021/ja00220a056

Cited by 52 publications

(31 citation statements)

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“…This implies that nucleophilic attack of the Cys-25 SH group occurs at the opposite side to the 0 atom of the oxirane ring plane, and attack from the same side causes electronic repulsion between the lone pairs of the Cys-25 Sy and oxirane 0 atoms. This configurational conversion has also been demonstrated by t3C-NMR spectroscopy [17].…”

Section: Resultssupporting

confidence: 52%

Mode of binding of E‐64‐c, a potent thiol protease inhibitor, to papain as determined by X‐ray crystal analysis of the complex

et al. 1989

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The three‐dimensional structure of the E‐64‐c‐papain complex has been determined by X‐ray crystal analysis at 2.5 Å resolution (conventional R = 26.9%). The structure determined indicates that: (i) the C2 atom of the oxirane ring of E‐64‐c is covalently bound by the Sγ atom of Cys‐25 of papain; (ii) this covalent bond formation results in a configurational conversion of the oxirane C2 atom from the S‐ to the R‐form; and (iii) extensive hydrogen bonding and hydrophobic interactions are responsible for the specific interaction of the E‐64‐c molecule with papain.

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Section: Resultssupporting

confidence: 52%

Mode of binding of E‐64‐c, a potent thiol protease inhibitor, to papain as determined by X‐ray crystal analysis of the complex

et al. 1989

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“…The compounds display no selectivity for calpain relative to the other cysteine proteases [47]. The mechanism for irreversible inactivation of cysteine proteases by epoxysuccinates and their mode of binding to cysteine proteases have been studied by NMR [51] and X-ray crystallography [52]. SAR studies of E-64 derivatives led to the following observations (Table 1): a).…”

Section: Calpain Inhibitors Derived From Plantsmentioning

confidence: 99%

A Survey of Calpain Inhibitors

Donkor¹

2000

CMC

136

153

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Calpain is unique among the cysteine protease family of enzymes in that it combines thiol protease activity with calmodulin-like activity. Despite its wide spread distribution the exact physiological function(s) of calpain is yet to be deciphered. The enzyme is however, implicated in a number of pathophysiological conditions. Due to the potential of calpain as a therapeutic target a number of inhibitors have been described for the enzyme. In this article we have grouped calpain inhibitors into those derived from natural sources, and those derived from chemical synthesis. Additionally, an overview of functional groups that have been used as warheads of calpain inhibitors is presented along with a discussion of the structure activity relationship studies of the address region of peptidyl calpain inhibitors. Recent work in this area has led to a better understanding of the structural requirements for tight binding of inhibitors to the active site of calpain. A discussion of peptidomimetic calpain inhibitors, nonpeptide calpain inhibitors, and selectivity of some calpain inhibitors are also presented. The recent disclosure of the crystal structure of a nonpeptide calpain inhibitor bound to a hydrophobic pocket on the calcium-binding domain of calpain has opened the door to future development of potent cell permeable nonpeptide calpain inhibitors.

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“…By NMR studies of the product formed on the inactivation of papain with a I3C-labeled derivative of Ep-475, it was concluded that the active center -SH group has bound to C-3 of the epoxide ring as shown (229). Model studies with benzyl mercaptan, : X= p o p a i n -~y s~~-0 which reacts at pH 10, showed attack at both C-2 and C-3, the latter being favored, however.…”

Section: -Cch-m-c-nh-0i-t-inhibitormentioning

confidence: 99%

Cysteinyl Proteinases and Their Selective Inactivation

Shaw

1990

Advances in Enzymology - And Related Areas of Molecular Biology

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Irreversible inhibition of papain by epoxysuccinyl peptides. Carbon-13 NMR characterization of the site of alkylation

Cited by 52 publications

References 0 publications

Mode of binding of E‐64‐c, a potent thiol protease inhibitor, to papain as determined by X‐ray crystal analysis of the complex

Mode of binding of E‐64‐c, a potent thiol protease inhibitor, to papain as determined by X‐ray crystal analysis of the complex

A Survey of Calpain Inhibitors

Cysteinyl Proteinases and Their Selective Inactivation

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