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2.16: The Natural Catalysts

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    Table 2.1 lists metalloenzymes that catalyze hydrolytic and related reactions. According to the above guidelines the hydrolysis of peptide bonds is catalyzed by enzymes called peptidases that belong to the class of hydrolases (according to the official enzyme classification). Two peptidases (carboxypeptidase and thermolysin) are known in great detail, because their structures have been elucidated by high-resolution x-ray crystallography. They share many features; e.g., their metal ions coordinate to the same kind of protein residues. A discussion of the possible mechanism of carboxypeptidase A will be given in Section V.A. Metallopeptidases are zinc enzymes: generally they are single polypeptide chains with molecular weights in the range 30 to 40 kDa. Metallohydrolases of carboxylic and phosphoric esters are also often zinc enzymes. Alkaline phosphatase will be described in Section V.B as a representative of this class. Magnesium is sometimes involved in hydrolytic reactions. This is common when phosphate groups are involved, probably because the affinity of Mg2+ for phosphate groups is high.1 However, hydrolytic reactions can be performed by other systems (not treated here) like urease, which contains nickel(II),2 or acid phosphatase, which contains two iron ions,3 or aconitase, which contains an Fe4S4 cluster.4

    Table 2.1 - Representative metalloenzymes catalyzing hydrolytic and related reactions
    Enzyme Metal(s) Function
    Carboxypeptidase Zn2+ Hydrolysis of C-terminal peptide residues
    Leucine aminopeptidases Zn2+ Hydrolysis of leucine N-terminal peptide residues
    Dipeptidase Zn2+ Hydrolysis of dipeptides
    Neutral protease Zn2+, Ca2+ Hydrolysis of peptides
    Collagenase Zn2+ Hydrolysis of collagen
    Phospholipase C Zn2+ Hydrolysis of phospholipids
    β-Lactamase II Zn2+ Hydrolysis of

    β-lactam ring

    Thermolysin Zn2+, Ca2+ Hydrolysis of peptides
    Alkaline phosphatase Zn2+, Mg2+ Hydrolysis of phosphate esters
    Carbonic anhydrase Zn2+ Hydration of CO2
    α-Amylase Ca2+, Zn2+ Hydrolysis of glucosides
    Phospholipase A2 Ca2+ Hydrolysis of phospholipids
    Inorganic pyrophosphatase Mg2+ Hydrolysis of pyrophosphate
    ATPase Mg2+ Hydrolysis of ATP
    Na+ - K+ - ATPase Na+, K+ Hydrolysis of ATP with transport of cations
    Mg2+ - Ca2+ - ATPase Mg2+, Ca2+ Hydrolysis of ATP with transport of cations
    Phosphatases Mg2+, Zn2+ Hydrolysis of phosphate esters
    Creatine kinase M2+ Phosphorylation of creatine
    Pyruvate kinase M+, M2+ Dephosphorylation of phosphoenolpyruvate
    Phosphoglucomutase Mg2+ Phosphate transfer converting glucose-I-phosphate to glucose-6-phosphate
    DNA polymerase Mg2+ ( Mn2+) Polymerization of DNA with formation of phosphate esters
    Alcohol dehydrogenase Zn2+ Hydride transfer from alcohols to NAD+

    Examples of enzymes catalyzing nucleophilic addition of OH- (other than hydrolysis) and H- are carbonic anhydrase and alcohol dehydrogenase. Both are zinc enzymes. In the official biochemical classification of enzymes, carbonic anhydrase belongs to the class of lyases. Lyases are enzymes that cleave C-C, C-O, C-N, or other bonds by elimination, leaving double bonds, or conversely add groups to double bonds. Carbonic anhydrase has a molecular weight around 30 kDa, and is among the most-studied metalloenzymes. It catalyzes the deceivingly simple CO2 hydration reaction. The subtleties of its biological function, unraveled by a combination of techniques, make it an ideal example for bioinorganic chemistry. Section IV is fully dedicated to this enzyme. Alcohol dehydrogenase is a 90-kDa enzyme that catalyzes the reversible transfer of a hydride ion from alcohols to NAD+. Although it is a redox enzyme (in fact, classified as an oxidoreductase) and not a hydrolytic one, it will illustrate a different use that Nature makes of zinc to catalyze nucleophilic attack at carbon (Section V.C). Finally, the enzymatic transfer of organic radicals by enzymes involving coenzyme B12 will be briefly considered.

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