Structure and function of malic enzymes, a new class of oxidative decarboxylases

被引:200
作者
Chang, GG [1 ]
Tong, L
机构
[1] Natl Yang Ming Univ, Proteome Res Ctr, Inst Biochem, Fac Life Sci, Taipei 112, Taiwan
[2] Columbia Univ, Dept Biol Sci, New York, NY 10027 USA
关键词
D O I
10.1021/bi035251+
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
Malic enzyme is a tetrameric protein with double dimer structure in which the dimer interface is more intimately contacted than the tetramer interface. Each monomeric unit of the enzyme is composed of four structural domains, which show a different folding topology from those of the other oxidative decarboxylases. The active center is located at the interface between domains B and C. For human mitochondrial malic enzyme, there is an exo nucleotide-binding site for the inhibitor ATP and an allosteric site for the activator fumarate, located at the tetramer and dimer interfaces, respectively. Crystal structures of the enzyme in various complexed forms indicate that the enzyme may exist in equilibrium among two open and two closed forms. Interconversion among these forms involves rigid-body movements of the four structural domains. Substrate binding at the active site shifts the open form to the closed form that represents an active site closure. Fumarate binding at the allosteric site induces the interconversion between forms I and II, which is mediated by the movements of domains A and D. Structures of malic enzyme from different sources are compared with an emphasis on the differences and their implications to structure-function relationships. The binding modes of the substrate, product, cofactors, and transition-state analogue at the active site, as well as ATP and fumarate at the exo site and allosteric site, respectively, provide a clear account for the catalytic mechanism, nucleotide specificities, allosteric regulation, and functional roles of the quaternary structure. The proposed catalytic mechanism involves tyrosine-112 and lysine-183 as the general acid and base, respectively. In addition, a divalent metal ion (Mn2+ or Mg2+) is essential in helping the catalysis. Binding of the metal ion also plays an important role in stabilizing the quaternary structural integrity of the enzyme.
引用
收藏
页码:12721 / 12733
页数:13
相关论文
共 63 条
[11]   Involvement of Phe(19) in the Mn2+-L-malate binding and the subunit interactions of pigeon liver malic enzyme [J].
Chou, WY ;
Liu, MY ;
Huang, SM ;
Chang, GG .
BIOCHEMISTRY, 1996, 35 (30) :9873-9879
[12]   Functional roles of the N-terminal amino acid residues in the Mn(II)-L-malate binding and subunit interactions of pigeon liver malic enzyme [J].
Chou, WY ;
Huang, SM ;
Chang, GG .
PROTEIN ENGINEERING, 1997, 10 (10) :1205-1211
[13]   CRYSTALLIZATION OF THE NAD-DEPENDENT MALIC ENZYME FROM THE PARASITIC NEMATODE ASCARIS-SUUM [J].
CLANCY, LL ;
RAO, GSJ ;
FINZEL, BC ;
MUCHMORE, SW ;
HOLLAND, DR ;
WATENPAUGH, KD ;
KRISHNAMURTHY, HM ;
SWEET, RM ;
COOK, PF ;
HARRIS, BG ;
EINSPAHR, HM .
JOURNAL OF MOLECULAR BIOLOGY, 1992, 226 (02) :565-569
[14]   Mechanisms of enzymatic oxidative decarboxylation [J].
Cleland, WW .
ACCOUNTS OF CHEMICAL RESEARCH, 1999, 32 (10) :862-868
[15]   Crystal structure of the malic enzyme from Ascaris suum complexed with nicotinamide adenine dinucleotide at 2.3 Å resolution [J].
Coleman, DE ;
Rao, GSJ ;
Goldsmith, EJ ;
Cook, PF ;
Harris, BG .
BIOCHEMISTRY, 2002, 41 (22) :6928-6938
[16]   NADP-malic enzyme from plants: a ubiquitous enzyme involved in different metabolic pathways [J].
Drincovich, MF ;
Casati, P ;
Andreo, CS .
FEBS LETTERS, 2001, 490 (1-2) :1-6
[17]  
Frenkel R, 1975, Curr Top Cell Regul, V9, P157
[18]   ConSurf: Identification of Functional Regions in Proteins by Surface-Mapping of Phylogenetic Information [J].
Glaser, F ;
Pupko, T ;
Paz, I ;
Bell, RE ;
Bechor-Shental, D ;
Martz, E ;
Ben-Tal, N .
BIOINFORMATICS, 2003, 19 (01) :163-164
[19]  
Goodridge AG, 1996, PROG NUCLEIC ACID RE, V52, P89, DOI 10.1016/S0079-6603(08)60965-4
[20]   Pyruvate carboxylation in neurons [J].
Hassel, B .
JOURNAL OF NEUROSCIENCE RESEARCH, 2001, 66 (05) :755-762