A schematic model for the allosteric activation of tyrosine hydroxylase

Abstract

Tyrosine hydroxylase activity is stimulated in vitro by a variety of seemingly unrelated compounds. These compounds include: 1) anions and polyanions such as heparin, polyglutamic acid and melanin (Kuczenski and Mandell, 1972; Katz et al., 1976; Nagatsu et al., 1978); 2) phospholipids (Lloyd and Kaufman, 1974; Raese et al., 1976; Lloyd, 1979); 3) ATP, Mg⁺⁺ and cyclic AMP dependent protein kinase (Harris et al., 1974; Lovenberg et al., 1975); and 4) limited proteolysis (Kuczenski, 1973). The activation exhibited by these modulators is suprisingly similar, suggesting that a common mechanism might be involved (Katz et al., 1976; Weiner et al., 1978). For example, phospholipid activation and exposure to phosphorylating conditions result in a form of tyrosine hydroxylase that has a decreased K_m for pterin cofactor with no change in the V_max. Under conditions of maximal activation, the pH optimum of the enzyme is shifted from 6.2 to 6.4–6.8 (Lloyd and Kaufman, 1975; Weiner et al., 1978). The similarity of the kinetic changes may be explained by the ability of these agents to cause the tyrosine hydroxylase molecule to assume a common conformation.