Proline residues catalysis

The catalytic machinery of COMT. Shown are the COMT residues important for catalysis, Mg2+ binding, the catechol as substrate, and the methyl-donating coenzyme AdoMet. The hydrophobic walls are defined by two tryptophane residues and a proline residue. 

All human metalloendoproteinases are metzincins, named for a downstream methionine residue involved in regulating catalysis by mediating a critical turn that brings an adjacent tyrosine or proline residue close to the catalytic zinc ion. Matrilysins (also called matrix metalloendoproteinases, MMPs) are the major class of metzincin endopeptidases involved in collagen and stromal degradation. The other two classes, adantalysins and... 

Another residue of demonstrated importance for catalysis is Pro-285, since a change to leucine in a C. acremonium sprantaneous mutant resulted in a total loss of activity (48). Moreover, this residue is invariably present in all of the prokaryotic and fungal genes (Figure 4). However, the precise role of this proline residue in the IPNS reaction is not clear at present. 

Proline is one amino acid which would be expected to profoundly influence the reactivity of a peptide substrate. Proline restricts the possible conformations of a peptide chain and in addition is unable to act as a hydrogen bond donor. Both of these factors could affect peptide bond cleavage by hindering substrate binding or by preventing proper catalysis. Alternately, favorable interaction could take place between the enzyme and a prolyl residue, due either to a favorable hydrophobic interaction with the prolyl side chain or because proline restricts the peptide conformation to one which is favorable. That these effects are important is accentuated by the fact that at every subsite the cleavage probability of a substrate with a proline residue is significantly different from the mean (0.148). This is true for no other amino acid residue. Proline is favorable at P4 and P3 and unfavorable at all other subsites (P2 P3) ... 

The catalytic site of protein tyrosine phosphatases has a conserved sequence motif, H/V-C—(X)5 -R-S/T-G/A/P, where X is any amino-acid residue H is histidine V, valine C, cysteine R, arginine S, serine T, threonine G, glycine A, alanine and P, proline. The cysteine in this site is involved in catalysis, in binding and removing the phosphate group of the substrate. 

The carboxyl-terminal extension of class II enzymes forms a hemicir-cular bannister around the calcium-binding loop. It is secured proximally (Cys-126 = Cys-27) and distally (Cys-134 = Cys-50) by disulfide bridges. The 7- or 8-residue loop is rich in prolines and charged residues. This substructure is remote from the residues implicated in interfacial ad-sorpdon, substrate binding, and catalysis and has no defined catalytic or pharmacological role. 

It should be noted that, even though chiral proline was used in the second example, only residual enantioselectivity was observed. The first two examples are typical enamine organocatalysis the third example [96] probably involves a Baylis-Hillman type mechanism (nucleophilic catalysis). 

A wide range of small organic molecules, mainly secondary amines such as proline derivatives, promote asymmetric aldol reactions through enamine catalysis [6]. List, Reymond, Gong, and others reported the first examples of peptidic catalysts for aldol reactions [7]. In their report, Reymond and coworkers [7a] developed two classes of peptides, following two different designs. In the first peptide class a primary amine is present as a side chain residue (similar to the natural type I aldolase) or as free N-terminus in the second a secondary amine or a proHne residue is present at the N-terminus of the peptide, which incorporated at least one free carboxyhc function (Figure 5.3). 

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