Novel mitochondrial complex II isolated from Trypanosoma cruzi is composed of 12 peptides including a heterodimeric Ip subunit.
Mitochondrial respiratory enzymes play a central role in energy production in aerobic organisms. They differentiated from the alpha-proteobacteria-derived ancestors by adding noncatalytic subunits. An exception is Complex II (succinate: ubiquinone reductase), which is composed of four alpha-proteobacteria-derived catalytic subunits (SDH1-SDH4). Complex II often plays a pivotal role in adaptation of parasites in host organisms and would be a potential target for new drugs. We purified Complex II from the parasitic protist Trypanosoma cruzi and obtained the unexpected result that it consists of six hydrophilic (SDH1, SDH2N, SDH2C, and SDH5-SDH7) and six hydrophobic (SDH3, SDH4, and SDH8-SDH11) nucleus-encoded subunits. Orthologous genes for each subunit were identified in Trypanosoma brucei and Leishmania major. Notably, the iron-sulfur subunit was heterodimeric; SDH2N and SDH2C contain the plant-type ferredoxin domain in the N-terminal half and the bacterial ferredoxin domain in the C-terminal half, respectively. Catalytic subunits (SDH1, SDH2N plus SDH2C, SDH3, and SDH4) contain all key residues for binding of dicarboxylates and quinones, but the enzyme showed the lower affinity for both substrates and inhibitors than mammalian enzymes. In addition, the enzyme binds protoheme IX, but SDH3 lacks a ligand histidine. These unusual features are unique in the Trypanosomatida and make their Complex II a target for new chemotherapeutic agents.
Morales
Jorge
J
Department of Biomedical Chemistry, Graduate School of Medicine, the University of Tokyo, Hongo, Bunkyo-ku, Tokyo 113-0033, USA.
Mogi
Tatsushi
T
Mineki
Shigeru
S
Takashima
Eizo
E
Mineki
Reiko
R
Hirawake
Hiroko
H
Sakamoto
Kimitoshi
K
Omura
Satoshi
S
Kita
Kiyoshi
K
D000818:Animals; D020134:Catalytic Domain / Q000502:physiology; D014355:Chagas Disease / Q000178:diet therapy / Q000201:enzymology; D015195:Drug Design; D042967:Electron Transport Complex I / Q000037:antagonists & inhibitors / Q000302:isolation & purification / Q000378:metabolism; D042963:Electron Transport Complex II / Q000037:antagonists & inhibitors / Q000302:isolation & purification / Q000378:metabolism*; D004791:Enzyme Inhibitors / Q000627:therapeutic use; D057927:Hydrophobic and Hydrophilic Interactions; D018320:Leishmania major / Q000201:enzymology; D008928:Mitochondria / Q000201:enzymology*; D024101:Mitochondrial Proteins / Q000037:antagonists & inhibitors / Q000302:isolation & purification / Q000378:metabolism*; D015800:Protozoan Proteins / Q000037:antagonists & inhibitors / Q000302:isolation & purification / Q000378:metabolism*; D014346:Trypanosoma brucei brucei / Q000201:enzymology; D014349:Trypanosoma cruzi / Q000201:enzymology*
D004791:Enzyme Inhibitors; D024101:Mitochondrial Proteins; D015800:Protozoan Proteins; D042963:Electron Transport Complex II; D042967:Electron Transport Complex I