A member of a family of sulfate-activating enzymes causes murine brachymorphism.
Sulfation is critical to the function of a wide variety of biomolecules. This common modification requires the enzymatic synthesis of an activated sulfate donor, phosphoadenosine-phosphosulfate (PAPS). In higher organisms PAPS synthesis is catalyzed by a bifunctional sulfurylase kinase (SK) polypeptide having both ATP-sulfurylase and adenosine-phosphosulfate kinase activities. We report the identification of a gene family encoding murine SK proteins with these two activities. A family member, SK2, colocalizes with the locus for the autosomal recessive murine phenotype brachymorphism. Brachymorphic mice have normal lifespans, but abnormal hepatic detoxification, bleeding times, and postnatal growth, the latter being attributed to undersulfation of cartilage proteoglycan. A missense mutation in the SK2 coding sequence of bm mice that alters a highly conserved amino acid residue destroys adenosine-phosphosulfate kinase activity and therefore the ability of SK2 to synthesize PAPS. We conclude that a family of SK genes are responsible for sulfate activation in mammals, that a mutation in SK2 causes murine brachymorphism, and that members of this gene family have nonredundant, tissue-specific roles.
Departments of Pediatrics and Biochemistry and Molecular Biology, University of Chicago, MC 5058, 5825 S. Maryland Avenue, Chicago, IL 60637, USA.
K
K
Kurima
M L
ML
Warman
S
S
Krishnan
M
M
Domowicz
R C
RC
Krueger
A
A
Deyrup
N B
NB
Schwartz
D000595:Amino Acid Sequence; D000818:Animals; D001483:Base Sequence; D001842:Bone and Bones / Q000002:abnormalities*; D002874:Chromosome Mapping; D003001:Cloning, Molecular; D018076:DNA, Complementary; D051379:Mice; D008969:Molecular Sequence Data; D009097:Multienzyme Complexes / Q000235:genetics* / Q000378:metabolism; D010724:Phosphoadenosine Phosphosulfate / Q000096:biosynthesis; D017853:Phosphotransferases (Alcohol Group Acceptor) / Q000235:genetics* / Q000378:metabolism; D011994:Recombinant Proteins / Q000235:genetics; D013430:Sulfate Adenylyltransferase / Q000235:genetics* / Q000378:metabolism
D018076:DNA, Complementary; D009097:Multienzyme Complexes; D011994:Recombinant Proteins; C113697:sulfurylase kinase; D010724:Phosphoadenosine Phosphosulfate; D017853:Phosphotransferases (Alcohol Group Acceptor); D013430:Sulfate Adenylyltransferase