1LI4

Human S-adenosylhomocysteine hydrolase complexed with neplanocin

Summary for 1LI4

• Entry DOI: 10.2210/pdb1li4/pdb
• Descriptor: S-adenosylhomocysteine hydrolase, NICOTINAMIDE-ADENINE-DINUCLEOTIDE, 3-(6-AMINO-PURIN-9-YL)-5-HYDROXYMETHYL-CYCLOPENTANE-1,2-DIOL, ... (5 entities in total)
• Functional Keywords: alpha-beta structure, inhibitor complex, hydrolase
• Biological source: Homo sapiens (human)
• Cellular location: Cytoplasm: P23526
• Total number of polymer chains: 1
• Total formula weight: 48821.84

Authors

Yang, X.,Hu, Y.,Yin, D.H.,Turner, M.A.,Wang, M.,Borchardt, R.T.,Howell, P.L.,Kuczera, K.,Schowen, R.L. (deposition date: 2002-04-17, release date: 2003-05-20, Last modification date: 2023-08-16)

Primary citation

Yang, X.,Hu, Y.,Yin, D.H.,Turner, M.A.,Wang, M.,Borchardt, R.T.,Howell, P.L.,Kuczera, K.,Schowen, R.L.
Catalytic strategy of S-adenosyl-L-homocysteine hydrolase: Transition-state stabilization and the avoidance of abortive reactions
Biochemistry, 42:1900-1909, 2003

PubMed Abstract: S-Adenosylhomocysteine hydrolase (AdoHcy hydrolase) crystallizes from solutions containing the intermediate analogue neplanocin A with the analogue bound in its 3'-keto form at the active sites of all of its four subunits and the four tightly bound cofactors in their reduced (NADH) state. The enzyme is in the closed conformation, which corresponds to the structure in which the catalytic chemistry occurs. Examination of the structure in the light of available, very detailed kinetic studies [Porter, D. J., Boyd, F. L. (1991) J. Biol. Chem. 266, 21616-21625. Porter, D. J., Boyd, F. L. (1992) J. Biol. Chem. 267, 3205-3213. Porter, D. J. (1998) J. Biol. Chem. 268, 66-73] suggests elements of the catalytic strategy of AdoHcy hydrolase for acceleration of the reversible conversion of AdoHcy to adenosine (Ado) and homocysteine (Hcy). The enzyme, each subunit of which possesses a substrate-binding domain that in the absence of substrate is in rapid motion relative to the tetrameric core of the enzyme, first binds substrate and ceases motion. Probably concurrently with oxidation of the substrate to its 3'-keto form, the closed active site is "sealed off" from the environment, as indicated by a large (10(8)(-)(9)-fold) reduction in the rate of departure of ligands, a feature that prevents exposure of the labile 3'-keto intermediates to the aqueous environment. Elimination of the 5'-substituent (Hcy in the hydrolytic direction, water in the synthetic direction) generates the central intermediate 4',5'-didehydro-5'-deoxy-3'-ketoadenosine. Abortive 3'-reduction of the central intermediate is prevented by a temporary suspension of all or part of the redox catalytic power of the enzyme during the existence of the central intermediate. The abortive reduction is 10(4)-fold slower than the productive reductions at the ends of the catalytic cycle and has a rate constant similar to those of nonenzymic intramolecular model reactions. The mechanism for suspending the redox catalytic power appears to be a conformationally induced increase in the distance across which hydride transfer must occur between cofactor and substrate, the responsible conformational change again being that which "seals" the active site. The crystal structure reveals a well-defined chain of three water molecules leading from the active site to the subunit surface, which may serve as a relay for proton exchange between solvent and active site in the closed form of the enzyme, permitting maintenance of active-site functional groups in catalytically suitable protonation states.

PubMed: 12590576
DOI: 10.1021/bi0262350

Experimental method

X-RAY DIFFRACTION (2.01 Å)