Aspartic acid biochemical structure

The elucidation of the X-ray structure of chymotrypsin (Ref. 1) and in a later stage of subtilisin (Ref. 2) revealed an active site with three crucial groups (Fig. 7.1)-the active serine, a neighboring histidine, and a buried aspartic acid. These three residues are frequently called the catalytic triad, and are designated here as Aspc Hisc Serc (where c indicates a catalytic residue). The identification of the location of the active-site groups and intense biochemical studies led to several mechanistic proposals for the action of serine proteases (see, for example, Refs. 1 and 2). However, it appears that without some way of translating the structural information to reaction-potential surfaces it is hard to discriminate between different alternative mechanisms. Thus it is instructive to use the procedure introduced in previous chapters and to examine the feasibility of different... 

The number of known or presumed mononuclear, non-heme iron oxygenases and related enzymes continues to grow. This is due to intensive biochemical research and especially based on sequence data derived from genome research projects i.14). For several of these enzymes structural data are available by now from protein crystallography (12-14). In many of the iron oxygenases the iron is facially bound by two histidines and one carboxylate donor, either glutamic acid or aspartic acid. Thus, the term 2-His-l-carboxylate facial triad has been introduced by L. Que Jr. for this motif (19). 

One remarkable feature of the nonnucleoside RT inhibitors when compared to their nucleoside counterparts is the selectivity they exhibit for HIV-1 RT compared to HIV-2 RT. They are typically inactive against HIV-2 RT whereas nucleoside inhibitors (as their triphosphates) are usually equally effective against both enzymes. Efforts to understand this phenomenon involved biophysical and structural studies to identify the binding site occupied by NNRTIs. Biochemical studies showed that the NNRTIs are noncompetitive inhibitors of RT, thus indicating that they do not compete with substrates at the enzyme active site. Photoaffmity labeling experiments identified two tyrosine residues, namely tyrosines 181 and 188 as components of the NNRTI binding site. In sequence, these tyrosine residues are close to aspartic acid residues 185 and 186, which constitute part of the enzyme active site. Subsequently, cocrystal X-ray pictures of RT with nevirapine (Figure 19.29) and with other inhibitors provided a more detailed structural perspective on the interactions of the NNRTIs and RT. 

M. A. Noble, S. Gul, C. S. Verma, and K. Brocklehurst, Biochem. J., 351, 732 (2000). Ionization Characteristics and Chemical Influences of Aspartic Acid Residue 158 of Papain and Caricain Determined by Structure-Related Kinetic and Computational Techniques Multiple Electrostatic Modulators and Active-Centre Chemistry. 

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