Metal-Dependent Function of a Mammalian Acireductone Dioxygenase

被引:30
作者
Deshpande, Aditi R. [1 ]
Wagenpfeil, Karina [2 ]
Pochapsky, Thomas C. [1 ,3 ,4 ]
Petsko, Gregory A. [1 ,3 ,5 ]
Ringe, Dagmar [1 ,3 ,4 ]
机构
[1] Brandeis Univ, Dept Biochem, Waltham, MA 02454 USA
[2] Brandeis Univ, Dept Biol, Waltham, MA 02454 USA
[3] Brandeis Univ, Dept Chem, Waltham, MA 02454 USA
[4] Brandeis Univ, Rosenstiel Inst Basic Biomed Res, Waltham, MA 02454 USA
[5] Weill Cornell Med Coll, Helen & Robert Appel Alzheimers Dis Res Inst, New York, NY 10065 USA
基金
美国国家科学基金会; 美国国家卫生研究院;
关键词
METHIONINE SALVAGE PATHWAY; CARBON BOND-CLEAVAGE; PROTEIN; IDENTIFICATION; APOPTOSIS; DERIVATIZATION; PERFORMANCE; EXPRESSION; PRECURSOR; RESPONSES;
D O I
10.1021/acs.biochem.5b01319
中图分类号
Q5 [生物化学]; Q7 [分子生物学];
学科分类号
071010 ; 081704 ;
摘要
The two acireductone dioxygenase (ARD) isozymes from the methionine salvage pathway of Klebsiella oxytoca are the only known pair of naturally occurring metalloenzymes with distinct chemical and physical properties determined solely by the identity of the divalent transition metal ion (Fe2+ or Ni2+) in the active site. We now show that this dual chemistry can also occur in mammals. ARD from Mus musculus (MmARD) was studied to relate the metal ion identity and three-dimensional structure to enzyme function. The iron-containing isozyme catalyzes the cleavage of 1,2-dihydroxy-3-keto-S-(thiomethyl)pent-1-ene (acireductone) by O-2 to formate and the ketoacid precursor of methionine, which is the penultimate step in methionine salvage. The nickel-bound form of ARD catalyzes an off-pathway reaction resulting in formate, carbon monoxide (CO), and 3-(thiomethyl). propionate. Recombinant MmARD was expressed and purified to obtain a homogeneous enzyme with a single transition metal ion bound. The Fe2+-bound protein, which shows about 10-fold higher activity than that of others, catalyzes on-pathway chemistry, whereas the Ni2+, Co2+, or Mn2+ forms exhibit off-pathway chemistry, as has been seen with ARD from Klebsiella. Thermal stability of the isozymes is strongly affected by the metal ion identity, with Ni2+-bound MmARD being the most stable, followed by Co2+ and Fe2+, and Mn2+-bound ARD being the least stable. Ni2+- and Co2+-bound MmARD were crystallized, and the structures of the two proteins found to be similar. Enzyme-ligand complexes provide insight into substrate binding, metal coordination, and the catalytic mechanism.
引用
收藏
页码:1398 / 1407
页数:10
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