Endothiapepsin

ENDOPOLYGALACTURONIDASE ENDOPOLYPHOSPHATASE Endoskeleton and exoskeleton, BIOMINERALIZATION ENDOTHERMIC PROCESS ENTHALRY EXOTHERMIC ENDOGONIC ENDOERGIC ENDOTHIAPEPSIN Endo-1,4-/J-xylanase,... 

Renin is a member of the homologous group of enzymes known as aspartic proteinases that includes pepsin and a group of fungal enzymes such as endothiapepsin, penicillopepsin, and rhizopuspepsin. 

Incorporation of glycol or vicinal diol analogs of the peptide bond (-CH(OH)-CH(OH)-) has led to potent inhibitors and the x-ray structure for one such compound complexed with endothiapepsin is available [27]. The first hydroxyl in... 

The catalytic mechanism proposed by Veerapandian et al. [31] based on the x-ray structure of a difluoroketone (geminal-diol) inhibitor bound to endothiapepsin. A water molecule tightly bound to the aspartates in the native enzyme is proposed to nucleophilically attack the scissile-bond carbonyl. The resulting geminal-diol intermediate is stabilised by hydrogen bonds with the negatively charged carboxyl of aspartate 32. 

The active-site cleft has a less open arrangement in renins than in the other aspartic proteinases. Many loops as well as the helix hc (residues 224-236) belonging to the C-domain (residues 190-302) are significantly closer to the active site in the renin structures compared to those of endothiapepsin-inhibitor complexes. This is partly due to a difference in relative position of the rigid body comprising the C-domain. For instance, there is a domain rotation of 4° and translation of 0.1 A in the human renin complex with respect to the endothiapepsin-difluorostatone complex. 

There is also great similarity between aspartic proteinases in terms of interactions with the transition-state analog inhibitors at the catalytic center. The catalytic aspartyl side chains and the inhibitor hydroxyl group are essentially superimposable in both renin complexes. The isostere C-OH bonds lie at identical positions when the structures of inhibitor complexes of several aspartic proteinases are superposed, in spite of the differences in the sequence and secondary structure. Most of the complex array of hydrogen bonds found in endothiapepsin complexes are formed in renin with the exception of that to the threonine or serine at 218, which is replaced by alanine in human renin. The similarity can be extended to all other pepsin-like aspartic proteinases and even to the retroviral proteinases [44,45]. This implies that the recognition of the transition state is conserved in evolution, and the mechanisms of this divergent group of proteinases must be very similar. 

Cooper J, Quail W, Frazao C, Foundling SI, Blundell TL. X-ray crystallographic analysis of inhibition of endothiapepsin by cyclohexyl renin inhibitors. Biochemistry 1992 31 8142-8150. 

The amino acid sequences of aspergillopepsin I, penicillopepsin, rhizopuspepsin, endothiapepsin, candidapepsin, mucorpepsin, porcine pepsin, and human cathepsin D are aligned. These enzymes are classified into two groups (class I and II). Class I enzymes have... 

In addition to the recombinant chymosin, several coagulants for cheese-making are available from microbial origin. These are endopro-teases from Rhizomucor miehei, Rhizomucor pussilus, and incidentally the plant-derived endothiapepsin from Cryphonectria parasitica. 

Figure 15 Neutron difference map showing the active site region of endothiapepsin (an aspartate protease) complexed with a transition state analogue. In this 2.1 A resolution neutron study hy Myles et al., Asp32 was foimd to he in its deprotonated state, while Asp215 is protonated. (Reprinted with permission from Coates, Erskine, Wood, Myles and Cooper. 2001 American Chemical Society)...

Table 1 Correlations of binding affinity prediction for seven published knowledge-based scoring functions for the PMF validation sets of 77 protein-ligand complexes (all) which consist of five classes [47] 16 serine protease (Ser), 15 metalloprotease (Met), 18 L-arabinose binding protein (L-ara), 11 endothiapepsin (End), and 17 diverse protein-ligand complexes (Oth)... 

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