Metal-Requiring Enzymes (Molecular Biology)

Enzymes that require metal ions for their catalytic activity fall into two classes. They are the metal-activated enzymes and the metalloenzymes. The latter contain tightly bound metals that do not dissociate during isolation or dialysis of the enzyme under conditions where activity is retained. However, such metal ions can be removed under more drastic conditions, such as low pH. Bound metal ions can be involved with the maintenance of the structural integrity of enzymes, and they can participate in electrophilic catalysis.

Metal ions that are found in metalloenzymes include those of the first transition series of elements in the periodic table:tmp4-6_thumbas well astmp4-7_thumb. Examples of enzymes that contain metal ions are listed in Table 1. Metal ions involved with enzymes that participate in electron transport undergo redox reactions. Thus, the ionic forms of iron, copper, cobalt, and molybdenum can betmp4-8_thumbrespectively.

For convenience, these metal ions will be listed simply as bivalent ions. Fe is most commonly found as a heme complex in redox enzymes such as catalase and peroxidases (see Iron-Binding Proteins). It also occurs as a component of iron-sulfur clusters in enzymes that are involved in one-electron transfer processes; NADH dehydrogenase and succinate dehydrogenase belong to this group and are flavoprotein enzymes. Liketmp4-9_thumbhas multivalent oxidation states, and many Cu enzymes are either oxidases or hydrolases that utilize molecular oxygen. Co enzymes, such as methylmalonyl-CoA mutase and ribonucleotide reductase, have the cobalt atom bound within a corrin ring. Ni is rarely found as a component of metalloenzymes, but urease from jack bean is an exception. The occurrence of Mn and Ca in metalloenzymes is also somewhat rare (see Calcium-Binding Proteins). Mg , the alkaline earth metal that is found so commonly in biological systems, does not play a role in the functioning of metalloenzymes, but is important in metal- activated enzymes (see below). By contrast, Zn is an important and widely utilized metal for electrophilic catalysis (see Zinc-Binding Proteins). Not all enzymes that catalyze a particular reaction have the same requirement for a metal. Thus, fructose bisphosphate aldolase from yeast and bacteria utilize Zn ions, whereas the same enzyme from muscle uses a Schiff Base intermediate to activate the substrate (1).

Table 1. Selected Examples of Metalloenzymes

Metal Ion



amylase, galactosyltransferase, thermolysin


dioldehydrase, glycerol dehydratase, methylmalonyl-CoAmutase, ribonucleotide reductase


cytochrome c oxidase, dopamine-b-hydroxylase,superoxide dismutase


catalase, NADH dehydrogenase, nitrogenase, peroxidase, succinate dehydrogenase, xanthine oxidase


arginase, histidine-ammonia lyase, pyruvate carboxylase


nitrogenase, xanthine oxidase


urease, Ni-Fe hydrogenase


alcohol dehydrogenase, carbonic anhydrase, carboxypeptidase, superoxide dismutase, thermolysin

The largest group of metal-activated enzymes contains the phosphotransferases that catalyze the transfer of the terminal phosphoryl group of ATP to an acceptor molecule that can be an alcohol, carboxylic acid, nitrogenous compound, or a phosphorylated compound (see Kinase). Their essential requirement for a bivalent metal ion is always satisfied by Mg or Mn . However, other bivalent metal ions have been shown to activate some phosphotransferases (2). The role of bivalent metal ions in the activation of phosphotransferases is to form a MgATP complex that then acts as the true substrate for the reaction. Thus, the binary complex formed by the interaction of the enzyme and its nucleotide substrate is an enzyme-nucleotide-metal complex. Some phosphotransferases involve a second metal ion that is liganded by the enzyme as well as the substrate. Examples are pyruvate kinase and the biotin-containing enzymes that form carboxybiotin by the initial phosphorylation of bicarbonate to carboxy-phosphate (1). Pyruvate kinase also differs from most other phosphotransferases in its requirement for K and its inhibition, rather than activation, by Ca .

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