ISOENZYMES AND ONTOGENY
Authors: MASTERS COLIN J. , HOLMES ROGER S. 
Published: January 2008

Summary1. In this review, representative data on the nature of enzyme multiplicity and the developmental progressions of multiple enzyme forms have been collected, and the significance of this material has been discussed in relation to gene involvement during tissue differentiation.2. In addition, emphasis has been directed towards the relevance of this onto‐genetic information to a wide variety of biological phenomena, such as the possibilities of metabolic advantage conferred by the distinctive properties and physiological locations of these multiple enzyme forms, the insight into the subunit structure and compositional interrelationships of proteins, the aetiology of disease states, the relationship to hormone action, the extra nuclear specification of enzymes, and the transformations between particulate and soluble enzymes.3. Three isoenzyme systems in particular have been chosen for the special development of these themes and treated in some detail; lactate dehydrogenase (LDH), aldolase and the esterases. Briefer accounts of the ontogeny of other less‐studied series of multiple enzyme forms have also been included.4. In relation to LDH, the major findings and conclusions of the pioneering investigators have been outlined, together with the reassessments which have been necessitated by recent studies of LDH ontogeny. It is evident, for example, that the early embryonic form of this enzyme is not necessarily parental as previously thought, and the realization appears to possess wide‐ranging implications in regard to the control of synthesis of the enzymes. An indirect role of oxygen in LDH biosynthesis is indicated together with the independent regulation of the separate genes.5. Recent developments in the enzymology of preimplantation ova have been discussed. It is noteworthy that the extraordinary levels of LDH activity which have been reported to be associated with these early developmental stages, may arise by extracellular adsorption rather than by an intrinsic synthesis of enzyme. Hence contemporary interest in this area has shifted towards a comprehension of the biochemical significance of the extremely unusual, selective concentrations of extracellular lactate dehydrogenase in the oviduct, the relation of this enzyme to the specialized growth requirements of the ova, and the influences of reproductive hormones on these oviducal isoenzymes.6. The role of aldolase ontogeny as well as the composition, gene control, and native state of these lysases is also reviewed. This enzyme provides a particular example of the manner in which tissue modification of the catalytic and structural properties of enzymes may influence interpretations of the native state of purified proteins, and in this case, also, the observable microheterogeneity satisfies previous disquietude in regard to the existence of different subunits in the muscle enzyme.7. The basic developmental importance of aldolase‐C is stressed by the occurrence of this form of the enzyme in the early embryos of many different species. Furthermore, a significant addition to our knowledge of the possible biological purposes of isoenzymes and the rationale of their ontogenetic development during the establishment of tissue identity would appear to follow from the recent studies on reversible adsorption of aldolase to cell membranes. Aldolase‐C. for example, is differentially inhibited in this way by the end product of anaerobic glycolysis, and other such metabolite‐isoenzyme‐tissue interactions allow for a wide range of tissue‐specific responses regulating energy derivation and other important functions of the cell.8. The remarkable extent of heterogeneity among the esterases, the distinctive species‐specific nature of their multiplicity, and the overlapping substrate specificities have long presented a formidable barrier to the unravelling of the isoenzyme status of these enzymes. The advantages of systematic approaches utilizing differential substrate and inhibitor specificities have been emphasized, and the most recently available information summarized.9. The carboxylesterases may be divided into five distinct groups, and recognizable subdivisions also occur within the other classes of esterases. Most of the different possibilities of isoenzyme causation are exemplified within the esterases, and the ontogenetic specificity of their heteromorphs seems to be greater than for any other recorded isoenzymic system.10. In addition to the generative features displayed by the ‘soluble’ enzyme forms, the potential utility of latent isoenzyme activities have been illustrated by reference to catalase. The properties of such systems provide a useful means of studying such problems as the subcellular specification of enzyme synthesis and the nature of the mechanism governing the distribution of specific proteins between organelles and cytosol.11. Catalase also provides a situation of special interest in that the existence of isoenzymes and even of activity in the cytosol have been disputed until very recently. Evidence establishing the reality of these occurrences, and the epigenetic nature of catalase multiplicity in some species, has been cited.12. Recently available ontogenetic information of a number of oxidoreductases, transferases and hydrolases has also been collected together and discussed.