Peptide bonds stereospecificity

Stereospecific enzymes catalyse reactions with one type of optical isomer but may also react with a series of related compounds of the same configuration. Many proteolytic enzymes hydrolyse only peptide bonds linking laevorotatory (L-) amino acids. 

Bacteria with surface polypeptides composed of D-amino acids are resistant to degradation because the proteases, the enzymes that immune system cells use to degrade protein in foreign cells, can only catalyze the hydrolysis of peptide bonds between L-amino acids. In other words, the active sites of proteases are stereospecific, i.e., they can only effectively bind peptides composed of L-amino acids. 

Phe, D-Phe and D-Phe ierf-butyl ester. The enzyme was not active toward L-Phe methyl ester, (L-Phe)2 methyl ester, (L-Phe)4, Boc-(L-Phe)4, Boc-(L-Phe)4 methyl ester, (D-VaDa, (D-Leu)2, or (D-Ala)n (n = 2 - 5). These properties indicated that the enzyme is an endopeptidase that acts D-stereospecifically upon peptides composed of aromatic D-amino acids. On the other hand, a dimer was formed when D-Phe methyl ester and D-Phe amide were the substrates. Eight stereoisomers of Phe trimer were synthesized, and their effectiveness as substrates for the enzyme was tested. The enzyme recognized the configuration of the second D-Phe of tripeptides and catalyzed the hydrolysis of the second peptide bond from the N-terminus. The calculated Vmax/Km values for the peptides containing L-Phe were lower than that for (D-Phels, affected by the configuration of the neighboring L-Phe. The enzyme also showed P-lactamase activity toward ampicillin and penicillin G. The calculated Vmax values of the enzyme for b-lactam compounds were about the same as those for (D-Phe)3 and (D-Phe)4, while the Km values were several hundred times larger. On the other hand, carboxypeptidase DD and D-aminopeptidase activities were undetectable. 

Another example of the ability of proteinogenic amino acids, small peptides, and amines to catalyse the formation of new C-C bonds has been demonstrated by Weber and Pizzarello they were able to carry out model reactions for the stereospecific synthesis of sugars (tetroses) using homochiral L-dipeptides. The authors achieved a D-enantiomeric excess (ee) of more than 80% using L-Val-L-Val as the peptide catalyst in sugar synthesis (in particular D-erythrose) via self-condensation of glycol aldehyde. 

Baldwin and Christie (18) have proposed that the origin of this difference almost certainly derives from a stereoelectronic factor. In 64 and 65, the Cg - S bond is more nearly orthogonal to the B-lactam amide plane than the C — S bons is, with respect to the thiazolidine amide plane (cf. 66). The Cg - S bond is therefore weaker than the CA - S bond and is preferentially cleaved. With tricyclic a-lactam 61, due to the five-membered ring, the C - S bond becomes more nearly orthogonal to the thiazolidine amide plane (cf. 67). As a consequence, the ordering of bond lability is reversed and the C — S bond is cleaved more readily. The stereoelectronically controlled step 61 63 has led to a stereospecific synthesis of a penicillin derivative from a peptide precursor. 

The carrier transport pathway is stereospecific (Matthews, 1975, 1983 Boyd and Ward, 1982 Asatoor et al, 1973 Cheeseman and Smyth, 1972) peptides of the D-configuration are handled by the transporter (Boyd and Ward, 1982 Asatoor et al, 1973 Cheeseman and Smyth, 1972) but are poorly taken up and slowly hydrolyzed (Matthews, 1975, 1983). An a-pepti bond is preferred (Matthews, 1975, 1983), though not required (Bai et al, 1991) for carrier transport, whereas methylation, acetylation, or other modification of the N-terminal a-amino group (Addison et al, 1974 Das and Radhakrishnan, 1975 Rubino et al, 1971 Addison et al, 1975), as well... 

SCHEME 47.40. Synthesis of dinucleoside vinylphosphonate-peptide conjugate employing stereospecific C—P bond-forming cross-coupling as a key step. 

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