Isoenzyme alleles

Ethnic differences in CYP2D6 have been more thoroughly documented than with the other isoenzyme (Bradford, 2002). Over 70% of Caucasians but only about half of Asians, Sub-Saharan Africans, and African Americans have fully functional CYP2D6 alleles - alleles that code for normal metabolic activity. Approximately 50% of Asian and people of African ancestry have reduced function or nonfunctioning alleles. As a consequence, many older psychotropic medications are metabolized more slowly and plasma levels would be higher. Thus individuals of African and Asian ancestry would have an increased risk of side effects and should receive lower dose for a therapeutic response when compared to Caucasians of European descent (Lin, 2001 Lawson, 2000). 

Gene frequencies and allelic mutations for ADH vary considerably and significant interpersonal and ethnic variations have been described. Furthermore, functional ADH is a dimer, usually of identical subunits but heterodimers are also possible and to date approximately 20 ADH isoenzymes are known. There are notable kinetic differences between the various functional ADH isoenzymes for example, Km values differ almost 1000-fold and Vmax by approximately 40-fold (see Table 6.4). These differences account, to some extent, for variation in alcohol tolerance between individuals. 

Another isoenzyme with substantial interest is erythrocytic acid phosphatase (EAP) (8, 9, 10). This system has three autosomal allelic genes termed A, B and C. These can be homozygous or heterozygous giving rise to BA, CA and CB phenotypes. Each of these phenotypes is easily distinguished using starch gel electrophoresis with very useful population frequencies of approximately A - 13%, B - 35%, C - 0.2%, BA - 43%, CA - 3%,... 

Another category of multiple molecular forms can arise when enzymes are ofigomeric and consist of molecules made up of subunits. The association of different types of subunits in various combinations gives rise to a range of active enzyme molecules. When the subunits are derived from different structural genes, either multiple loci or multiple alleles, the hybrid molecules so formed are called hybrid isoenzymes. The ability to form hybrid isoenzymes is evidence of considerable structural similarities between the different subunits. Hybrid isoenzymes can be formed in vitro, but they are also formed in vivo in cells in which the different types of constituent subunits are present in the same sub-ceUular compartment. 

A number of isoenzymes that are related to GST p have since been identified. A hepatic enzyme, called GST ip, has been purified in several laboratories (H27, S26), and it has been shown that this homodimeric protein has an N-terminal amino acid sequence identical to that of GST p (All, HI 6). The expression of this additional mu-class form in human liver is also subject to variation (H63). GST p and GST op are homodimers and it is now generally accepted that these two enzymes represent allelic variants encoded at the GST 1 locus identified by Board (B30) and Strange et al. (S41). Less information is available on the heterodimeric enzyme formed by the combination of p-type and ip-type subunits (H16, V4). The existence of this isoenzyme has been demonstrated by means of starch-gel electrophoresis and chromatofocusing (F2, S41) however, so far, it has not been fully characterized. A third hepatic mu-class enzyme, named GST < ), was identified by Stockman and Hayes (S36). This isoenzyme, which was present in only 1 of 20 livers examined, was shown to be immunologically related to GST p and GST ip but could be distinguished from these forms by its lower isoelectric point and the fact that, unlike GST p and GST ip, it has a blocked N terminus (P. 

Isozymes or isoenzymes, are enzymes that differ in amino acid sequence yet catalyze the same reaction. Usually, these enzymes display different kinetic parameters, such as K, or different regulatory properties. They are encoded by different genetic loci, which usually arise through gene duplication and divergence (Section 2.2.5). Isozymes differ from allozymes, which are enzymes that arise from allelic variation at one gene locus. Isozymes can often be distinguished from one another by biochemical properties such as electrophoretic mobility. 

Lavie, B., Eviatar, N., 1987. Differential fitness of allelic isoenzymes in the marine gastropods Littorina punctata and L neritoides exposed to the environmental stress of the combined effects of cadmium and mercury pollution. Environ. Manag. 11, 345-350. 

In the case of Triticum it is probable that the loci Adh-1 and Adh-2 each code independently for polypeptides which subsequently associate to dimers. At locus Adh-1 most probably two codominant alleles Adh-li and Adh-lj exist and are, together with Adh-2 responsible for an isoenzyme pattern such as is schematically represented in Table II. 

In the case of the field mouse Peromyscus maniculatus, Shaw and Barto (1963) demonstrated in allelic variant of the locus Ldh-b, which they called Ldh-b. Heterozygotes for this locus produce the fifteen predictable tetramers formed by combination of three subunits A, B, and B. Here multiple gene loci as well as different alleles at these loci are responsible for the formation of isoenzymes. 

Model fob the Role of the Alleles of the Adh-1 Gene Locus of Triticum dicoccum in the Genetic Control of Dimeric ADH Isoenzymes"... 

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