Ch

COO— Succinate

The enzyme that catalyzes this reversible reaction is called succinyl-CoA synthetase or succinic thioki-

nase; both names indicate the participation of a nucle-oside triphosphate in the reaction (Box 16-1).

This energy-conserving reaction involves an intermediate step in which the enzyme molecule itself becomes phosphorylated at a His residue in the active site (Fig. 16-12a). This phosphoryl group, which has a high group transfer potential, is transferred to ADP (or GDP) to form ATP (or GTP). Animal cells have two isozymes of succinyl-CoA synthetase, one specific for ADP and the other for GDP. The enzyme has two subunits, a (Mr 32,000), which has the (P)-His residue (His246) and the binding site for CoA, and 3 (Mr 42,000), which confers specificity for either ADP or GDP. The active site is at the interface between subunits. The crystal structure of succinyl-CoA synthetase reveals two "power helices" (one from each subunit), oriented so that their electric dipoles situate partial positive charges close to the negatively charged (P)-His (Fig. 16-12b), stabilizing the phosphoenzyme intermediate. (Recall the similar role of helix dipoles in stabilizing K+ ions in the K+ channel (see Fig. 11-48).)

FIGURE 16-12 The succinyl-CoA synthetase reaction. (a) In step (( a phosphoryl group replaces the CoA of succinyl-CoA bound to the enzyme, forming a high-energy acyl phosphate. In step (2 the suc-cinyl phosphate donates its phosphoryl group to a His residue on the enzyme, forming a high-energy phosphohistidyl enzyme. In step (3) the phosphoryl group is transferred from the His residue to the terminal phosphate of GDP (or ADP), forming GTP (or ATP). (b) Succinyl-CoA synthetase of E. coli (derived from PDB ID 1SCU). The bacterial and mammalian enzymes have similar amino acid sequences and presumably have very similar three-dimensional structures. The active site includes part of both the a (blue) and 3 (brown) subunits. The power helices (bright blue, dark brown) situate the partial positive charges of the helix dipole near the phosphate group (orange) on His246 of the a chain, stabilizing the phosphohistidyl enzyme. Coenzyme A is shown here as a red stick structure. (To improve the visibility of the power helices, some nearby secondary structures have been made transparent.)

Succinyl-CoA synthetase

Succinyl-CoA

Succinyl-CoA synthetase

S-CoA

S-CoA

CoA-SH

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