TY  - CHAP
M1  - Book, Section
TI  - Xanthine Oxidoreductase—Role in Human Pathophysiology and in Hereditary Xanthinuria
A1  - Raivio, Kari O.
A1  - Saksela, Mika
A1  - Lapatto, Risto
A2  - Valle, David L.
A2  - Antonarakis, Stylianos
A2  - Ballabio, Andrea
A2  - Beaudet, Arthur L.
A2  - Mitchell, Grant A.
PY  - 2019
T2  - The Online Metabolic and Molecular Bases of Inherited Disease
AB  - Xanthine  oxidoreductase  (XOR)  catalyzes  the  final  reactions  of  the  purine  catabolic  pathway,  oxidizing  hypoxanthine  to  xanthine  and  xanthine  to  uric  acid.  Inherited  deficiency  of  the  enzyme  results  in  xanthinuria  (MIM  278300),  which  is  usually  clinically  mild  or  asymptomatic.  Precipitation  of  xanthine  in  the  urinary  tract  or  muscle  may  give  rise  to  the  most  common  symptoms,  urolithiasis  (with  secondary  renal  damage)  and  muscle  pain.  Biochemically  the  disease  is  characterized  by  low  uric  acid  and  elevated  xanthine  in  plasma  and  urine.  Xanthinuria  is  an  autosomal  recessive  disease.In  addition  to  hypoxanthine  and  xanthine,  XOR  oxidizes  adenine,  6-mercaptopurine,  and  allopurinol;  a  number  of  pyrimidines,  aldehydes,  and  pterins  are  also  substrates.  Under  physiological  conditions,  XOR  functions  mainly  as  a  dehydrogenase,  with  NAD+  as  the  cosubstrate,  but  it  can  be  converted  into  an  oxidase,  which  utilizes  molecular  oxygen  as  the  cosubstrate  and  produces  hydrogen  peroxide  and  superoxide.  The  enzyme  may  also  form  nitric  oxide  by  reducing  nitrite  or  by  cleaving  nitrosothiols.  The  Km  values  of  both  the  dehydrogenase  and  the  oxidase  for  the  purine  substrates  are  in  the  range  of  10−6–10−5  M.Reversible  conversion  of  xanthine  dehydrogenase  into  oxidase  occurs  by  sulfhydryl  group  oxidation,  which  results  in  loss  of  the  NAD+  binding  site.  Irreversible  proteolytic  conversion  into  oxidase  occurs  upon  enzyme  purification,  tissue  ischemia,  or  treatment  with  proteolytic  enzymes.  In  cell  and  tissue  extracts,  7–35  percent  of  total  enzyme  activity  is  accounted  for  by  the  oxidase.  Inactive  enzyme  forms  include  desulfo-XOR  and  demolybdo-XOR.The  human  XOR  gene  is  located  on  chromosome  2p22,  spans  at  least  60  kb,  and  consists  of  36  exons  and  35  introns.  The  cDNA  for  human  xanthine  dehydrogenase  corresponds  to  a  polypeptide  of  1333  amino  acids,  with  a  predicted  molecular  weight  of  ∼146  kDa.  Purified  human  XOR  is  a  dimer  of  two  identical  subunits  of  ∼150  kDa.  Each  subunit  consists  of  three  domains,  cleavable  by  proteolysis  but  remaining  associated  under  nondenaturing  conditions.  The  N-terminal  20-kDa  domain  contains  two  nonidentical  Fe-S  centers,  the  middle  40-kDa  domain  contains  an  FAD  center,  and  the  C-terminal  85-kDa  domain  contains  molybdenum  bound  to  a  cofactor.  Catalysis  is  initiated  by  the  transfer  of  two  electrons  to  the  Mo(VI)  atom,  followed  by  intramolecular  electron  transfer  to  the  Fe-S  centers  and  finally  to  FAD,  which  is  then  oxidized  by  either  NAD+  or  oxygen.  Allopurinol  inhibits  the  enzyme  after  being  converted  into  oxypurinol,  which  binds  tightly  to  the  molybdenum  center.Enzyme  activity,  immunoreactive  protein,  and  mRNA  of  XOR  are  abundantly  expressed  in  human  proximal  small  intestine  and  liver;  low  activity  is  inconsistently  present  in  kidney  and  lung.  Immunohistochemistry  shows  expression  in  intestinal  epithelial  cells  and  hepatocytes,  faintly  in  other  organs'  capillary  endothelial  cells.  Resting  mammary  epithelium  contains  enzyme  protein,  which  increases  during  lactation.  No  activity,  protein,  or  mRNA  can  be  detected  in  human  myocardium  or  brain.  Basal  expression  is  increased  during  hypoxia  by  posttranslational  mechanisms.  Hyperoxia  suppresses  enzyme  activity  by  inactivation  of  the  enzyme  protein  and  by  inhibition  of  transcription.  Several  cytokines  (e.g.,  γ-interferon)  activate  transcription.  Nitric  oxide  donors  and  NO  itself  suppress  XOR  activity.Xanthine  oxidase  has  been  ascribed  a  role  in  ischemia-reperfusion  damage.  Hypoxanthine  and  xanthine  ...
SN  - 
PB  - McGraw-Hill Education
CY  - New York, NY
Y2  - 2024/04/20
UR  - ommbid.mhmedical.com/content.aspx?aid=1181441307
ER  -