Oxalate synthesis in mammals: properties and subcellular distribution of serine:pyruvate/alanine:glyoxylate aminotransferase in the liver.
Primary hyperoxaluria Type 1 (PH1) is caused by a functional deficiency of a liver enzyme, serine:pyruvate/alanine:glyoxylate aminotransferase (SPT/AGT), which catalyzes transamination between L-serine or l-alanine as an amino acid substrate and glyoxylate or pyruvate as an alpha-keto acid substrate. A high affinity for glyoxylate is a notable feature of this enzyme, suggesting a role in glyoxylate metabolism in vivo. Another conspicuous feature of SPT/AGT is its species-specific and food habit-dependent subcellular distribution. Thus, the enzyme is located in peroxisomes in herbivores and man, largely in mitochondria in carnivores, and in both the organelles in rodents. The mechanism of the species-specific dual organelle localization of SPT/AGT is either transcription of the gene from two different start sites or loss of the upstream translation initiation ATG codon by mutations. It appears that the mitochondrial versus peroxisomal distribution of SPT/AGT in different animal species is indispensable in meeting the metabolic needs caused by their respective food habits. As for the peroxisomal localization, glycolate is contained in plants much more than in animal tissues, and when ingested, it is converted to glyoxylate, an immediate precursor of oxalate, in liver peroxisomes. Therefore, peroxisomal localization of SPT/AGT may be indispensable for herbivores to convert the glyoxylate formed in peroxisomes into glycine in situ rather than forming oxalate. On the other hand, our recent studies showed that SPT/AGT contributed substantially to serine metabolism in rabbit, human, and dog livers; i.e., irrespective of its mitochondrial or peroxisomal localization. Thus, the mitochondrial localization of SPT/AGT was not a prerequisite for the metabolism of L-serine. Another source of glyoxylate is the metabolism of L-hydroxyproline, and in this case, the enzyme responsible for the glyoxylate formation has been reported to be a mitochondrial matrix enzyme. Collagen accounts for about 30% of total animal proteins and contains about 13% (w/w) hydroxyproline. It is therefore possible that both mitochondrial and peroxisomal SPT/AGT contribute to the metabolism of glyoxylate and serine, but the subcellular site for glyoxylate metabolism is different in herbivores and carnivores.
Ichiyama
A
A
First Department of Biochemistry, Hamamatsu University School of Medicine, Shizuoka, Japan. ichiyama@hama-med.ac.jp
Xue
H H
HH
Oda
T
T
Uchida
C
C
Sugiyama
T
T
Maeda-Nakai
E
E
Sato
K
K
Nagai
E
E
Watanabe
S
S
Takayama
T
T
D000818:Animals; D001483:Base Sequence; D015152:Blotting, Northern; D019556:COS Cells; D004285:Dogs; D006038:Glyoxylates / Q000378:metabolism; D006801:Humans; D006909:Hydroxyproline / Q000378:metabolism; D007700:Kinetics; D008099:Liver / Q000378:metabolism*; D008954:Models, Biological; D008969:Molecular Sequence Data; D010070:Oxalates / Q000378:metabolism*; D011817:Rabbits; D051381:Rats; D012694:Serine / Q000378:metabolism; D013045:Species Specificity; D000637:Transaminases / Q000378:metabolism*
D006038:Glyoxylates; D010070:Oxalates; D012694:Serine; D000637:Transaminases; C019635:Alanine-glyoxylate transaminase; C022638:serine-pyruvate aminotransferase; C031150:glyoxylic acid; D006909:Hydroxyproline