Crystal structure of agmatinase reveals structural conservation and inhibition mechanism of the ureohydrolase superfamily.
Agmatine is the product of arginine decarboxylation and can be hydrolyzed by agmatinase to putrescine, the precursor for biosynthesis of higher polyamines, spermidine, and spermine. Besides being an intermediate in polyamine metabolism, recent findings indicate that agmatine may play important regulatory roles in mammals. Agmatinase is a binuclear manganese metalloenzyme and belongs to the ureohydrolase superfamily that includes arginase, formiminoglutamase, and proclavaminate amidinohydrolase. Compared with a wealth of structural information available for arginases, no three-dimensional structure of agmatinase has been reported. Agmatinase from Deinococcus radiodurans, a 304-residue protein, shows approximately 33% of sequence identity to human mitochondrial agmatinase. Here we report the crystal structure of D. radiodurans agmatinase in Mn(2+)-free, Mn(2+)-bound, and Mn(2+)-inhibitor-bound forms, representing the first structure of agmatinase. It reveals the conservation as well as variation in folding, oligomerization, and the active site of the ureohydrolase superfamily. D. radiodurans agmatinase exists as a compact homohexamer of 32 symmetry. Its binuclear manganese cluster is highly similar but not identical to the clusters of arginase and proclavaminate amidinohydrolase. The structure of the inhibited complex reveals that inhibition by 1,6-diaminohexane arises from the displacement of the metal-bridging water.
Ahn
Hyung Jun
HJ
Department of Chemistry, College of Natural Sciences, Seoul National University, Seoul 151-742, Korea.
Kim
Kyoung Hoon
KH
Lee
Jiah
J
Ha
Jun-Yong
JY
Lee
Hyung Ho
HH
Kim
Dojin
D
Yoon
Hye-Jin
HJ
Kwon
Ae-Ran
AR
Suh
Se Won
SW
D000376:Agmatine / Q000378:metabolism*; D000595:Amino Acid Sequence; D020134:Catalytic Domain; D018360:Crystallography, X-Ray; D034301:Deinococcus / Q000737:chemistry / Q000201:enzymology / Q000378:metabolism; D008969:Molecular Sequence Data; D017434:Protein Structure, Tertiary; D014512:Ureohydrolases / Q000737:chemistry* / Q000378:metabolism
D000376:Agmatine; D014512:Ureohydrolases; C019625:agmatinase