Penicillin-recognizing proteins

Okazaki, S., Suzuki, A., Komeda, H., Yamaguchi, S., Asano, Y, and Yamane, T, "Crystal structure and functional characterization of a u-stereospecific amino acid amidase from Ochrobactrum anthropi SV3, a new member of the penicillin-recognizing proteins." /. Mol. Biol, 368, 79-91 (2007). 

The most common mechanism of bacterial resistance to P-lactam antibiotics such as the penicillins and cephalosporins is the synthesis of P-lactamases that cleave an amide bond in the antibiotics to generate inactive products (Wiedemann et al., 1989). Genes encoding P-lactamases can be found on the bacterial chromosome or on plasmids. The active site serine P-lactamases belong to a larger family of penicillin-recognizing enzymes that includes the penicillin binding proteins (Joris et al., 1988). All of these enzymes contain the active site serine as well as a conserved triad of K(S/T)G between the active site serine and the C-terminus (Joris et al, 1988). 

The predicted polypeptide was similar to carboxypeptidase DD from Streptomyces R61, penicillin-binding proteins from S. lactamdurans and B. subtilis, and class C p-lactamases. Thus, the enzyme was categorized as a new "penicillin-recognizing enzyme"... 

Penicillin is an unstable, reactive molecule which in the body can easily react with constituents of the cells and tissues such as proteins. The reaction with proteins will alter their structure. They may become sufficiently different to be recognized by the immune system, and the body then mounts an immune attack on these altered proteins (known as antigens). This process can take one of several forms. For example, if the penicillin reacts with the proteins on the outside of the red blood cell, these may be recognized by the immune system. The immune system then reacts by producing antibodies, specific proteins which will recognize and bind to the altered red cells. The next stage is when a type of white blood cell called a natural killer cell sees and binds to the antibody on the red cell and destroys the red cell. The result of this is haemolytic anaemia, in which the number of red blood cells is depleted, possibly to dangerous levels. 

There are really two factors to be considered. First, the capability of a particular drug to cause the event which I just described, and secondly the capability of a drug administered to a person in which this process has taken place to be immediately recognized as antigenic and to elicit an anaphylactic reaction. A number of different chemical reactions have been associated with this phenomenon. One of them is simple acylation of protein by the / -lactam. Inasmuch as the mechanism of action of both the penicillins and cephalosporins is also thought to involve acylation by the -lactam, I think that it is very unlikely that there will ever be a -lactam antibiotic which is active and which will not in some patients form antigenic material by this same mechanism. It is my impression that cephalosporins have a lesser tendency to sensitize than some penicillins and that not all penicillin-sensitive people react to a given cephalosporin. The differences are probably quantitative and will never be qualitative. 

The scale-up of fermentation processes as a central problem in biotechnology was hrst recognized and described during industrial penicillin production at the beginning of the 1940s and has been studied in more detail in E. coli and recombinant protein production. 

A hypothesis about the role of the 6(7)p-acylamino side-chain conformation should thus take into account the full set of available facts. Moreover, the excellent activity of some of the new bicyclic P-lactams (see elsewhere in these volumes) demonstrates that the 6(7)-acylamino substituent is not always an essential structural ingredient for antibacterial activity. It is likely that the 6(7)-acylamino group serves as an additional handle by which the receptor sites may recognize and anchor the p-lactam antibiotic in the active site. This handle is essential for p-lactams with the reactivity of penicillins and cephalosporins, but is superfluous or even detrimental in more reactive p-lactams, as discussed later. Undoubtedly, a better appreciation of the conformation of the side chains will be possible after X-ray elucidation of the three-dimensional structures of the p-lactam-binding proteins of bacteria vide infra). 

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