TY - JOUR
T1 - The structural biochemistry of the superoxide dismutases
AU - Perry, J. J.P.
AU - Shin, D. S.
AU - Getzoff, E. D.
AU - Tainer, J. A.
N1 - Funding Information:
We dedicate this review to all patients and their families, and the pioneering researchers in the SOD field, especially Irwin Fridovich and Joseph McCord, who discovered SOD activity; David and Jane Richardson, who tackled the three-dimensional structure of SOD; Stefan Marklund, who discovered SOD3; James Lepock, who characterized SOD stability; Robert Hallewell, who cloned human SOD1; Joan Valentine who characterized the Cu and Zn ion binding; Barry Halliwell, who characterized superoxide toxicity; Joseph Beckman and Bruce Freeman, who identified the cytotoxicity resulting from interactions of superoxide with nitric oxide; Danielle Touati, who used genetics to show the role of SOD in cells; Bernard Babior, who discovered superoxide in the oxidative burst of macrophages; Martha Ludwig, who characterized the first FeSOD structures; Teepu Siddique and Robert Brown, who identified SOD mutations in ALS patients; Don Cleveland, who identified aggregates containing SOD1 as common to FALS disease; and Larry Oberley who defined SOD roles in cancer. We thank Michael Pique for 30+ years of insightful SOD computer graphics, and members of the Tainer and the Getzoff laboratories at TSRI for their critical comments on this manuscript. Work on SOD in the authors' laboratories was funded by the National Institutes of Health (GM39345 and GM37684).
PY - 2010/2
Y1 - 2010/2
N2 - The discovery of superoxide dismutases (SODs), which convert superoxide radicals to molecular oxygen and hydrogen peroxide, has been termed the most important discovery of modern biology never to win a Nobel Prize. Here, we review the reasons this discovery has been underappreciated, as well as discuss the robust results supporting its premier biological importance and utility for current research. We highlight our understanding of SOD function gained through structural biology analyses, which reveal important hydrogen-bonding schemes and metal-binding motifs. These structural features create remarkable enzymes that promote catalysis at faster than diffusion-limited rates by using electrostatic guidance. These architectures additionally alter the redox potential of the active site metal center to a range suitable for the superoxide disproportionation reaction and protect against inhibition of catalysis by molecules such as phosphate. SOD structures may also control their enzymatic activity through product inhibition; manipulation of these product inhibition levels has the potential to generate therapeutic forms of SOD. Markedly, structural destabilization of the SOD architecture can lead to disease, as mutations in Cu,ZnSOD may result in familial amyotrophic lateral sclerosis, a relatively common, rapidly progressing and fatal neurodegenerative disorder. We describe our current understanding of how these Cu,ZnSOD mutations may lead to aggregation/fibril formation, as a detailed understanding of these mechanisms provides new avenues for the development of therapeutics against this so far untreatable neurodegenerative pathology.
AB - The discovery of superoxide dismutases (SODs), which convert superoxide radicals to molecular oxygen and hydrogen peroxide, has been termed the most important discovery of modern biology never to win a Nobel Prize. Here, we review the reasons this discovery has been underappreciated, as well as discuss the robust results supporting its premier biological importance and utility for current research. We highlight our understanding of SOD function gained through structural biology analyses, which reveal important hydrogen-bonding schemes and metal-binding motifs. These structural features create remarkable enzymes that promote catalysis at faster than diffusion-limited rates by using electrostatic guidance. These architectures additionally alter the redox potential of the active site metal center to a range suitable for the superoxide disproportionation reaction and protect against inhibition of catalysis by molecules such as phosphate. SOD structures may also control their enzymatic activity through product inhibition; manipulation of these product inhibition levels has the potential to generate therapeutic forms of SOD. Markedly, structural destabilization of the SOD architecture can lead to disease, as mutations in Cu,ZnSOD may result in familial amyotrophic lateral sclerosis, a relatively common, rapidly progressing and fatal neurodegenerative disorder. We describe our current understanding of how these Cu,ZnSOD mutations may lead to aggregation/fibril formation, as a detailed understanding of these mechanisms provides new avenues for the development of therapeutics against this so far untreatable neurodegenerative pathology.
KW - Amyotrophic lateral sclerosis
KW - Lou Gehrig's disease
KW - Protein crystallography
KW - Reactive oxygen species
KW - Superoxide dismutase
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U2 - 10.1016/j.bbapap.2009.11.004
DO - 10.1016/j.bbapap.2009.11.004
M3 - Review article
C2 - 19914407
AN - SCOPUS:74649085703
SN - 1570-9639
VL - 1804
SP - 245
EP - 262
JO - Biochimica et Biophysica Acta - Proteins and Proteomics
JF - Biochimica et Biophysica Acta - Proteins and Proteomics
IS - 2
ER -