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W1991782016 abstract "l-Serine metabolism in rabbit, dog, and human livers was investigated, focusing on the relative contributions of the three pathways, one initiated by serine dehydratase, another by serine:pyruvate/alanine:glyoxylate aminotransferase (SPT/AGT), and the other involving serine hydroxymethyltransferase and the mitochondrial glycine cleavage enzyme system (GCS). Under quasi-physiological in vitro conditions (1 mml-serine and 0.25 mmpyruvate), flux through serine dehydratase accounted for only traces, and that through SPT/AGT substantially contributed no matter whether the enzyme was located in peroxisomes (rabbit and human) or largely in mitochondria (dog). As for flux through serine hydroxymethyltransferase and GCS, the conversion of serine to glycine occurred fairly rapidly, followed by GCS-mediated slow decarboxylation of the accumulated glycine. The flux through GCS was relatively high in the dog and low in the rabbit, and only in the dog was it comparable with that through SPT/AGT. An in vivo experiment withl-[3-3H,14C]serine as the substrate indicated that in rabbit liver, gluconeogenesis froml-serine proceeds mainly via hydroxypyruvate. Because an important role in the conversion of glyoxylate to glycine has been assigned to peroxisomal SPT/AGT from the studies on primary hyperoxaluria type 1, these results suggest that SPT/AGT in this organelle plays dual roles in the metabolism of glyoxylate and serine. l-Serine metabolism in rabbit, dog, and human livers was investigated, focusing on the relative contributions of the three pathways, one initiated by serine dehydratase, another by serine:pyruvate/alanine:glyoxylate aminotransferase (SPT/AGT), and the other involving serine hydroxymethyltransferase and the mitochondrial glycine cleavage enzyme system (GCS). Under quasi-physiological in vitro conditions (1 mml-serine and 0.25 mmpyruvate), flux through serine dehydratase accounted for only traces, and that through SPT/AGT substantially contributed no matter whether the enzyme was located in peroxisomes (rabbit and human) or largely in mitochondria (dog). As for flux through serine hydroxymethyltransferase and GCS, the conversion of serine to glycine occurred fairly rapidly, followed by GCS-mediated slow decarboxylation of the accumulated glycine. The flux through GCS was relatively high in the dog and low in the rabbit, and only in the dog was it comparable with that through SPT/AGT. An in vivo experiment withl-[3-3H,14C]serine as the substrate indicated that in rabbit liver, gluconeogenesis froml-serine proceeds mainly via hydroxypyruvate. Because an important role in the conversion of glyoxylate to glycine has been assigned to peroxisomal SPT/AGT from the studies on primary hyperoxaluria type 1, these results suggest that SPT/AGT in this organelle plays dual roles in the metabolism of glyoxylate and serine. Among the three major enzymes involved in the metabolism ofl-serine in mammalian liver, l-serine dehydratase (SDH), 1The abbreviations used are: SDH, l-serine dehydratase (EC 4.2.1.13); SHMT, serine hydroxymethyltransferase (EC 2.1.2.1); mSHMT, mitochondrial isozyme of serine hydroxymethyltransferase; cSHMT, cytosolic isozyme of serine hydroxymethyltransferase; SPT/AGT, serine:pyruvate/alanine:glyoxylate aminotransferase (EC 2.6.1.51/EC 2.6.1.44); GCS, glycine cleavage enzyme system (EC 1.4.4.2-1.8.1.4-2.1.2.10); Mit-Ps, subcellular fraction containing mitochondria and peroxisomes. 1The abbreviations used are: SDH, l-serine dehydratase (EC 4.2.1.13); SHMT, serine hydroxymethyltransferase (EC 2.1.2.1); mSHMT, mitochondrial isozyme of serine hydroxymethyltransferase; cSHMT, cytosolic isozyme of serine hydroxymethyltransferase; SPT/AGT, serine:pyruvate/alanine:glyoxylate aminotransferase (EC 2.6.1.51/EC 2.6.1.44); GCS, glycine cleavage enzyme system (EC 1.4.4.2-1.8.1.4-2.1.2.10); Mit-Ps, subcellular fraction containing mitochondria and peroxisomes.serine:pyruvate/alanine:glyoxylate aminotransferase (SPT/AGT), and serine hydroxymethyltransferase (SHMT), the former two are thought to participate in gluconeogenesis from l-serine (1Snell K. Adv. Enzyme Regul. 1984; 22: 325-400Crossref PubMed Scopus (224) Google Scholar). Notable features of SPT/AGT are that this enzyme is located entirely in peroxisomes in herbivores and humans, largely in mitochondria in carnivores (2Takada Y. Noguchi T. Comp. Biochem. Physiol. 1982; 72B: 597-604Google Scholar, 3Noguchi T. Takada Y. J. Biol. Chem. 1978; 253: 7598-7600Abstract Full Text PDF PubMed Google Scholar, 4Danpure C.J. Guttridge K.M. Fryer P. Jennings P.R. Allsop J. Purdue P.E. J. Cell Sci. 1990; 97: 669-678Crossref PubMed Google Scholar), and in both organelles in rodents such as rat, and in the rat only the mitochondrial enzyme is induced by glucagon (5Oda T. Funai T. Ichiyama A. J. Biol. Chem. 1990; 265: 7513-7519Abstract Full Text PDF PubMed Google Scholar). It has been generally accepted from the known overproduction of oxalate in primary hyperoxaluria type 1, an inborn error of glyoxylate metabolism caused by a functional deficiency of peroxisomal SPT/AGT (6Danpure C.J. Purdue P.E. Scriver C.R. Beaudet A.L. Sly W.S. Valle D. 7th Ed. The Metabolic and Molecular Bases of Inherited Disease. 2. McGraw-Hill, New York1995: 2385-2424Google Scholar), that the enzyme in this organelle plays an important role in the conversion of glyoxylate to glycine, but the role of mitochondrial and peroxisomal SPT/AGT in the serine metabolism has not been elucidated. Cytosolic and mitochondrial isozymes of SHMT (cSHMT and mSHMT, respectively) have been shown to catalyze the interconversion between serine and glycine in conjugation with mitochondrial glycine cleavage enzyme system (GCS). This interconversion occurs especially when there is need for C1-substituted tetrahydrofolate cofactors or when either one of these amino acids are used or supplied (1Snell K. Adv. Enzyme Regul. 1984; 22: 325-400Crossref PubMed Scopus (224) Google Scholar). In the preceding paper (7Xue H.-H. Fujie M. Sakaguchi T. Oda T. Ogawa H. Kneer N.M. Lardy H.A. Ichiyama A. J. Biol. Chem. 1999; 274: 16020-16027Abstract Full Text Full Text PDF PubMed Scopus (38) Google Scholar), we considered SDH, SPT/AGT, and GCS to be the metabolic exits of the serine-glycine pool and showed that SDH is the major enzyme in the metabolism of l-serine in rat liver. The flux through SPT/AGT was enhanced by glucagon administration, but even after the induction, its contribution was about 110 of that through SDH both in vitro and in vivo. The flux through GCS was comparable with that through SPT/AGT in glucagon-treated rats (7Xue H.-H. Fujie M. Sakaguchi T. Oda T. Ogawa H. Kneer N.M. Lardy H.A. Ichiyama A. J. Biol. Chem. 1999; 274: 16020-16027Abstract Full Text Full Text PDF PubMed Scopus (38) Google Scholar). However, this pattern of l-serine metabolism in rat liver may not be extrapolated to other animals, because the SDH activity is known to decrease drastically as the body size of animals increases (8Rowsell E.V. Carnie J.A. Wahbi S.D. Al-Tai A.H. Rowsell K.V. Comp. Biochem. Physiol. 1979; 63B: 543-555Google Scholar). Although the results obtained with glucagon-treated rats suggested that mitochondrial SPT/AGT is involved in the metabolism ofl-serine, whether its contribution can be substantial and whether the enzyme in peroxisomes plays dual roles in the metabolism of glyoxylate and serine remain obscure. This paper deals with thel-serine metabolism in rabbit, dog, and human livers. Dog and rabbit were chosen as representatives of carnivores and herbivores, respectively.DISCUSSIONIn this study, we have presented in vitro and in vivo data suggesting that, in rabbit, dog, and human livers, SPT/AGT substantially contributes to the metabolism ofl-serine, whereas the contribution of SDH is fairly small. This pattern of l-serine metabolism is in contrast to the observation that in rat liver the contribution of SDH is the largest, and the flux through SPT/AGT accounts for only traces unless this enzyme has been induced by a previous administration of glucagon (7Xue H.-H. Fujie M. Sakaguchi T. Oda T. Ogawa H. Kneer N.M. Lardy H.A. Ichiyama A. J. Biol. Chem. 1999; 274: 16020-16027Abstract Full Text Full Text PDF PubMed Scopus (38) Google Scholar). Such species-specific patterns of the l-serine metabolism approximately agree with the observed activities of serine-metabolizing enzymes in respective animals (Table I). Our results are compatible with the observation by Rowsell et al. (8Rowsell E.V. Carnie J.A. Wahbi S.D. Al-Tai A.H. Rowsell K.V. Comp. Biochem. Physiol. 1979; 63B: 543-555Google Scholar) that in rabbit and dog livers the SPT/AGT activity is more than six times higher, and the SDH activity is much lower than the respective activities in rat liver.It is noteworthy that SPT/AGT is involved in the l-serine metabolism, no matter whether the enzyme is largely located in mitochondria (dog liver) or entirely in peroxisomes (rabbit and human livers). It has been expected that mitochondrial SPT/AGT plays a role in l-serine metabolism, because in the rat, the flux through SPT/AGT in gluconeogenesis from l-serine was apparent only when liver mitochondrial SPT/AGT had been induced by glucagon (7Xue H.-H. Fujie M. Sakaguchi T. Oda T. Ogawa H. Kneer N.M. Lardy H.A. Ichiyama A. J. Biol. Chem. 1999; 274: 16020-16027Abstract Full Text Full Text PDF PubMed Scopus (38) Google Scholar). This was corroborated in the present study by demonstrating in in vitro experiments under quasi-physiological conditions that the flux through SPT/AGT accounts for a large portion of l-serine metabolized in dog liver. These results are in accordance with the observation of Beliveau and Freedland (17Beliveau G.P. Freedland R.A. Comp. Biochem. Physiol. 1982; 71B: 13-18Google Scholar) that serine is mainly metabolized via transamination in hepatocytes isolated from the cat, another carnivore. As for the peroxisomal SPT/AGT, on the other hand, an important role in the conversion of glyoxylate to glycine has been indicated from the studies on primary hyperoxaluria type 1 (6Danpure C.J. Purdue P.E. Scriver C.R. Beaudet A.L. Sly W.S. Valle D. 7th Ed. The Metabolic and Molecular Bases of Inherited Disease. 2. McGraw-Hill, New York1995: 2385-2424Google Scholar). In the present study, the peroxisomal SPT/AGT was also shown to participate inl-serine metabolism in vitro (Table II). In addition, in the case of rabbit liver, an infusion experiment withl-[3-3H,14C]serine suggested that the flux through SPT/AGT contributes to gluconeogenesis froml-serine in vivo and accounts for as much as ∼90% of it (Table III). It is evident that peroxisomal SPT/AGT plays dual roles in the metabolism of serine and glyoxylate. It is possible, although it has not yet been experimentally proved, that mitochondrial SPT/AGT also plays a role in the metabolism of glyoxylate.l-Hydroxyproline has been shown to be metabolized to glyoxylate in mitochondria (or peroxisomes, 18,000 × gprecipitate; Ref. 18Maitra U. Pekker E.E. J. Biol. Chem. 1964; 237: 1485-1491Google Scholar), and glyoxylate thus formed was proposed to be converted to glycine by mitochondrial SPT/AGT, although the quantities of the hydroxyproline-derived glyoxylate must be small (1Snell K. Adv. Enzyme Regul. 1984; 22: 325-400Crossref PubMed Scopus (224) Google Scholar, 19Rowsell E.V. Snell K. Carnie J.A. Rowsell K.V. Biochem. J. 1972; 127: 155-165Crossref PubMed Scopus (44) Google Scholar). SPT/AGT is thus a unique enzyme of dual organelle localization, and it is possible that the enzyme in either organelle plays dual roles, gluconeogenesis from serine and conversion of glyoxylate to glycine by transamination. Such dual functions probably come from the fact that serine:glyoxylate aminotransferase (EC 2.6.1.45), the plant counterpart of animal SPT/AGT (EC 2.6.1.44/2.6.1.51), catalyzes transamination between serine and glyoxylate in the photorespiratory nitrogen cycle (20Keys A.J. Bird I.F. Cornelius M.J. Lea P.J. Wallsgrove R.M. Miflin B.J. Nature. 1978; 275: 741-743Crossref Scopus (328) Google Scholar), forming hydroxypyruvate and glycine, the latter being converted back to serine by a mitochondrial enzyme system. It is unlikely that glyoxylate is supplied in the animal livers as abundantly as in the photorespiration in plant leaves. Therefore, the hepatic serine metabolism catalyzed by SPT/AGT may not be necessarily coupled with the glyoxylate-to-glycine conversion, and more versatile pyruvate may also be used as an amino acceptor from serine, although the affinity of the enzyme for glyoxylate is much higher than that for pyruvate, as demonstrated by much lower K m for glyoxylate (10 μm) than that for pyruvate (480 μm) of the rat liver enzyme at pH 7.4 (21Yanagisawa M. Higashi S. Oda T. Ichiyama A. Lennone D.F. Stratman F.W. Zahtten R.N. Biochemistry of Metabolic Processes. Elsevier, Amsterdam1983: 413-426Google Scholar).Because plant tissues contain significant amounts of glycolate (22Harris K.S. Richardson K.E. Invest. Urol. 1980; 18: 106-109PubMed Google Scholar), and the conversion of glycolate to glyoxylate takes place in liver peroxisomes, the peroxisomal location of SPT/AGT may be favorable for herbivores to convert the glycolate-derived glyoxylate to glycine and to prevent harmful overproduction of oxalate. For carnivores, on the other hand, there may be less need of the peroxisomal location of SPT/AGT, because meats contain much less glycolate (22Harris K.S. Richardson K.E. Invest. Urol. 1980; 18: 106-109PubMed Google Scholar). With respect to its role in the disposal of serine demonstrated in this study, SPT/AGT in either of the two organelles appears to function with similar efficiency. Thus the necessity and advantages to carnivores of having SPT/AGT in mitochondria are not yet fully understood and need further studies.As for the metabolism of l-serine via glycine, the overall flux observed with reconstituted cytoplasmic extracts from rabbit, human, and dog livers was similar to that in the case of rat liver. As proposed in the preceding paper (7Xue H.-H. Fujie M. Sakaguchi T. Oda T. Ogawa H. Kneer N.M. Lardy H.A. Ichiyama A. J. Biol. Chem. 1999; 274: 16020-16027Abstract Full Text Full Text PDF PubMed Scopus (38) Google Scholar), the SHMT-catalyzed interconversion between serine and glycine may contribute, at least in part, to the maintaining of their intracellular concentration balance, in response to supply or use of these amino acids and tetrahydrofolate coenzymes, and the degradation of glycine by GCS may be considered as a metabolic exit of not only glycine but also l-serine. This view was further supported in the present study by showing that, irrespective of the animal species tested, the conversion of serine to glycine catalyzed by cSHMT occurred fairly rapidly, followed by the GCS-mediated slow decarboxylation of the accumulated glycine. However, the flux through GCS as well as that through SDH and SPT/AGT varied considerably from animal to animal. In dog liver in which the activity of GCS was relatively high, the contribution of the flux through GCS was comparable with that through SPT/AGT, but in rabbit and human livers the GCS pathway accounted for only a small portion ofl-serine metabolized (Table II). It has been previously noted that the activity of GCS is relatively small, and the apparent low activity may have some rationale, because glycine is an important amino acid that is used in many ways in the cells (12Kikuchi G. Mol. Cell. Biochem. 1973; 1: 169-187Crossref PubMed Scopus (252) Google Scholar). Although the flux through SPT/AGT is one of the major metabolic exits of serine in rabbit, human, and dog livers, its activity is also relatively small, consistent with the previous observation by Felig et al.(23Felig P. Owen O.E. Wahren J. Cahill Jr., G.F. J. Clin. Invest. 1969; 48: 584-593Crossref PubMed Scopus (481) Google Scholar) that serine, as well as glycine, is less effective than alanine as a precursor for hepatic gluconeogenesis in humans.Summarizing all the data and discussions presented in this paper together with those in the preceding one (7Xue H.-H. Fujie M. Sakaguchi T. Oda T. Ogawa H. Kneer N.M. Lardy H.A. Ichiyama A. J. Biol. Chem. 1999; 274: 16020-16027Abstract Full Text Full Text PDF PubMed Scopus (38) Google Scholar), we believe that SDH, SPT/AGT, cSHMT, mSHMT, and GCS work as schematically shown in Fig. 3 in the hepatic metabolism ofl-serine and glycine in rats, rabbits, humans, and dogs. Among the three major enzymes involved in the metabolism ofl-serine in mammalian liver, l-serine dehydratase (SDH), 1The abbreviations used are: SDH, l-serine dehydratase (EC 4.2.1.13); SHMT, serine hydroxymethyltransferase (EC 2.1.2.1); mSHMT, mitochondrial isozyme of serine hydroxymethyltransferase; cSHMT, cytosolic isozyme of serine hydroxymethyltransferase; SPT/AGT, serine:pyruvate/alanine:glyoxylate aminotransferase (EC 2.6.1.51/EC 2.6.1.44); GCS, glycine cleavage enzyme system (EC 1.4.4.2-1.8.1.4-2.1.2.10); Mit-Ps, subcellular fraction containing mitochondria and peroxisomes. 1The abbreviations used are: SDH, l-serine dehydratase (EC 4.2.1.13); SHMT, serine hydroxymethyltransferase (EC 2.1.2.1); mSHMT, mitochondrial isozyme of serine hydroxymethyltransferase; cSHMT, cytosolic isozyme of serine hydroxymethyltransferase; SPT/AGT, serine:pyruvate/alanine:glyoxylate aminotransferase (EC 2.6.1.51/EC 2.6.1.44); GCS, glycine cleavage enzyme system (EC 1.4.4.2-1.8.1.4-2.1.2.10); Mit-Ps, subcellular fraction containing mitochondria and peroxisomes.serine:pyruvate/alanine:glyoxylate aminotransferase (SPT/AGT), and serine hydroxymethyltransferase (SHMT), the former two are thought to participate in gluconeogenesis from l-serine (1Snell K. Adv. Enzyme Regul. 1984; 22: 325-400Crossref PubMed Scopus (224) Google Scholar). Notable features of SPT/AGT are that this enzyme is located entirely in peroxisomes in herbivores and humans, largely in mitochondria in carnivores (2Takada Y. Noguchi T. Comp. Biochem. Physiol. 1982; 72B: 597-604Google Scholar, 3Noguchi T. Takada Y. J. Biol. Chem. 1978; 253: 7598-7600Abstract Full Text PDF PubMed Google Scholar, 4Danpure C.J. Guttridge K.M. Fryer P. Jennings P.R. Allsop J. Purdue P.E. J. Cell Sci. 1990; 97: 669-678Crossref PubMed Google Scholar), and in both organelles in rodents such as rat, and in the rat only the mitochondrial enzyme is induced by glucagon (5Oda T. Funai T. Ichiyama A. J. Biol. Chem. 1990; 265: 7513-7519Abstract Full Text PDF PubMed Google Scholar). It has been generally accepted from the known overproduction of oxalate in primary hyperoxaluria type 1, an inborn error of glyoxylate metabolism caused by a functional deficiency of peroxisomal SPT/AGT (6Danpure C.J. Purdue P.E. Scriver C.R. Beaudet A.L. Sly W.S. Valle D. 7th Ed. The Metabolic and Molecular Bases of Inherited Disease. 2. McGraw-Hill, New York1995: 2385-2424Google Scholar), that the enzyme in this organelle plays an important role in the conversion of glyoxylate to glycine, but the role of mitochondrial and peroxisomal SPT/AGT in the serine metabolism has not been elucidated. Cytosolic and mitochondrial isozymes of SHMT (cSHMT and mSHMT, respectively) have been shown to catalyze the interconversion between serine and glycine in conjugation with mitochondrial glycine cleavage enzyme system (GCS). This interconversion occurs especially when there is need for C1-substituted tetrahydrofolate cofactors or when either one of these amino acids are used or supplied (1Snell K. Adv. Enzyme Regul. 1984; 22: 325-400Crossref PubMed Scopus (224) Google Scholar). In the preceding paper (7Xue H.-H. Fujie M. Sakaguchi T. Oda T. Ogawa H. Kneer N.M. Lardy H.A. Ichiyama A. J. Biol. Chem. 1999; 274: 16020-16027Abstract Full Text Full Text PDF PubMed Scopus (38) Google Scholar), we considered SDH, SPT/AGT, and GCS to be the metabolic exits of the serine-glycine pool and showed that SDH is the major enzyme in the metabolism of l-serine in rat liver. The flux through SPT/AGT was enhanced by glucagon administration, but even after the induction, its contribution was about 110 of that through SDH both in vitro and in vivo. The flux through GCS was comparable with that through SPT/AGT in glucagon-treated rats (7Xue H.-H. Fujie M. Sakaguchi T. Oda T. Ogawa H. Kneer N.M. Lardy H.A. Ichiyama A. J. Biol. Chem. 1999; 274: 16020-16027Abstract Full Text Full Text PDF PubMed Scopus (38) Google Scholar). However, this pattern of l-serine metabolism in rat liver may not be extrapolated to other animals, because the SDH activity is known to decrease drastically as the body size of animals increases (8Rowsell E.V. Carnie J.A. Wahbi S.D. Al-Tai A.H. Rowsell K.V. Comp. Biochem. Physiol. 1979; 63B: 543-555Google Scholar). Although the results obtained with glucagon-treated rats suggested that mitochondrial SPT/AGT is involved in the metabolism ofl-serine, whether its contribution can be substantial and whether the enzyme in peroxisomes plays dual roles in the metabolism of glyoxylate and serine remain obscure. This paper deals with thel-serine metabolism in rabbit, dog, and human livers. Dog and rabbit were chosen as representatives of carnivores and herbivores, respectively. DISCUSSIONIn this study, we have presented in vitro and in vivo data suggesting that, in rabbit, dog, and human livers, SPT/AGT substantially contributes to the metabolism ofl-serine, whereas the contribution of SDH is fairly small. This pattern of l-serine metabolism is in contrast to the observation that in rat liver the contribution of SDH is the largest, and the flux through SPT/AGT accounts for only traces unless this enzyme has been induced by a previous administration of glucagon (7Xue H.-H. Fujie M. Sakaguchi T. Oda T. Ogawa H. Kneer N.M. Lardy H.A. Ichiyama A. J. Biol. Chem. 1999; 274: 16020-16027Abstract Full Text Full Text PDF PubMed Scopus (38) Google Scholar). Such species-specific patterns of the l-serine metabolism approximately agree with the observed activities of serine-metabolizing enzymes in respective animals (Table I). Our results are compatible with the observation by Rowsell et al. (8Rowsell E.V. Carnie J.A. Wahbi S.D. Al-Tai A.H. Rowsell K.V. Comp. Biochem. Physiol. 1979; 63B: 543-555Google Scholar) that in rabbit and dog livers the SPT/AGT activity is more than six times higher, and the SDH activity is much lower than the respective activities in rat liver.It is noteworthy that SPT/AGT is involved in the l-serine metabolism, no matter whether the enzyme is largely located in mitochondria (dog liver) or entirely in peroxisomes (rabbit and human livers). It has been expected that mitochondrial SPT/AGT plays a role in l-serine metabolism, because in the rat, the flux through SPT/AGT in gluconeogenesis from l-serine was apparent only when liver mitochondrial SPT/AGT had been induced by glucagon (7Xue H.-H. Fujie M. Sakaguchi T. Oda T. Ogawa H. Kneer N.M. Lardy H.A. Ichiyama A. J. Biol. Chem. 1999; 274: 16020-16027Abstract Full Text Full Text PDF PubMed Scopus (38) Google Scholar). This was corroborated in the present study by demonstrating in in vitro experiments under quasi-physiological conditions that the flux through SPT/AGT accounts for a large portion of l-serine metabolized in dog liver. These results are in accordance with the observation of Beliveau and Freedland (17Beliveau G.P. Freedland R.A. Comp. Biochem. Physiol. 1982; 71B: 13-18Google Scholar) that serine is mainly metabolized via transamination in hepatocytes isolated from the cat, another carnivore. As for the peroxisomal SPT/AGT, on the other hand, an important role in the conversion of glyoxylate to glycine has been indicated from the studies on primary hyperoxaluria type 1 (6Danpure C.J. Purdue P.E. Scriver C.R. Beaudet A.L. Sly W.S. Valle D. 7th Ed. The Metabolic and Molecular Bases of Inherited Disease. 2. McGraw-Hill, New York1995: 2385-2424Google Scholar). In the present study, the peroxisomal SPT/AGT was also shown to participate inl-serine metabolism in vitro (Table II). In addition, in the case of rabbit liver, an infusion experiment withl-[3-3H,14C]serine suggested that the flux through SPT/AGT contributes to gluconeogenesis froml-serine in vivo and accounts for as much as ∼90% of it (Table III). It is evident that peroxisomal SPT/AGT plays dual roles in the metabolism of serine and glyoxylate. It is possible, although it has not yet been experimentally proved, that mitochondrial SPT/AGT also plays a role in the metabolism of glyoxylate.l-Hydroxyproline has been shown to be metabolized to glyoxylate in mitochondria (or peroxisomes, 18,000 × gprecipitate; Ref. 18Maitra U. Pekker E.E. J. Biol. Chem. 1964; 237: 1485-1491Google Scholar), and glyoxylate thus formed was proposed to be converted to glycine by mitochondrial SPT/AGT, although the quantities of the hydroxyproline-derived glyoxylate must be small (1Snell K. Adv. Enzyme Regul. 1984; 22: 325-400Crossref PubMed Scopus (224) Google Scholar, 19Rowsell E.V. Snell K. Carnie J.A. Rowsell K.V. Biochem. J. 1972; 127: 155-165Crossref PubMed Scopus (44) Google Scholar). SPT/AGT is thus a unique enzyme of dual organelle localization, and it is possible that the enzyme in either organelle plays dual roles, gluconeogenesis from serine and conversion of glyoxylate to glycine by transamination. Such dual functions probably come from the fact that serine:glyoxylate aminotransferase (EC 2.6.1.45), the plant counterpart of animal SPT/AGT (EC 2.6.1.44/2.6.1.51), catalyzes transamination between serine and glyoxylate in the photorespiratory nitrogen cycle (20Keys A.J. Bird I.F. Cornelius M.J. Lea P.J. Wallsgrove R.M. Miflin B.J. Nature. 1978; 275: 741-743Crossref Scopus (328) Google Scholar), forming hydroxypyruvate and glycine, the latter being converted back to serine by a mitochondrial enzyme system. It is unlikely that glyoxylate is supplied in the animal livers as abundantly as in the photorespiration in plant leaves. Therefore, the hepatic serine metabolism catalyzed by SPT/AGT may not be necessarily coupled with the glyoxylate-to-glycine conversion, and more versatile pyruvate may also be used as an amino acceptor from serine, although the affinity of the enzyme for glyoxylate is much higher than that for pyruvate, as demonstrated by much lower K m for glyoxylate (10 μm) than that for pyruvate (480 μm) of the rat liver enzyme at pH 7.4 (21Yanagisawa M. Higashi S. Oda T. Ichiyama A. Lennone D.F. Stratman F.W. Zahtten R.N. Biochemistry of Metabolic Processes. Elsevier, Amsterdam1983: 413-426Google Scholar).Because plant tissues contain significant amounts of glycolate (22Harris K.S. Richardson K.E. Invest. Urol. 1980; 18: 106-109PubMed Google Scholar), and the conversion of glycolate to glyoxylate takes place in liver peroxisomes, the peroxisomal location of SPT/AGT may be favorable for herbivores to convert the glycolate-derived glyoxylate to glycine and to prevent harmful overproduction of oxalate. For carnivores, on the other hand, there may be less need of the peroxisomal location of SPT/AGT, because meats contain much less glycolate (22Harris K.S. Richardson K.E. Invest. Urol. 1980; 18: 106-109PubMed Google Scholar). With respect to its role in the disposal of serine demonstrated in this study, SPT/AGT in either of the two organelles appears to function with similar efficiency. Thus the necessity and advantages to carnivores of having SPT/AGT in mitochondria are not yet fully understood and need further studies.As for the metabolism of l-serine via glycine, the overall flux observed with reconstituted cytoplasmic extracts from rabbit, human, and dog livers was similar to that in the case of rat liver. As proposed in the preceding paper (7Xue H.-H. Fujie M. Sakaguchi T. Oda T. Ogawa H. Kneer N.M. Lardy H.A. Ichiyama A. J. Biol. Chem. 1999; 274: 16020-16027Abstract Full Text Full Text PDF PubMed Scopus (38) Google Scholar), the SHMT-catalyzed interconversion between serine and glycine may contribute, at least in part, to the maintaining of their intracellular concentration balance, in response to supply or use of these amino acids and tetrahydrofolate coenzymes, and the degradation of glycine by GCS may be considered as a metabolic exit of not only glycine but also l-serine. This view was further supported in the present study by showing that, irrespective of the animal species tested, the conversion of serine to glycine catalyzed by cSHMT occurred fairly rapidly, followed by the GCS-mediated slow decarboxylation of the accumulated glycine. However, the flux through GCS as well as that through SDH and SPT/AGT varied considerably from animal to animal. In dog liver in which the activity of GCS was relatively high, the contribution of the flux through GCS was comparable with that through SPT/AGT, but in rabbit and human livers the GCS pathway accounted for only a small portion ofl-serine metabolized (Table II). It has been previously noted that the activity of GCS is relatively small, and the apparent low activity may have some rationale, because glycine is an important amino acid that is used in many ways in the cells (12Kikuchi G. Mol. Cell. Biochem. 1973; 1: 169-187Crossref PubMed Scopus (252) Google Scholar). Although the flux through SPT/AGT is one of the major metabolic exits of serine in rabbit, human, and dog livers, its activity is also relatively small, consistent with the previous observation by Felig et al.(23Felig P. Owen O.E. Wahren J. Cahill Jr., G.F. J. Clin. Invest. 1969; 48: 584-593Crossref PubMed Scopus (481) Google Scholar) that serine, as well as glycine, is less effective than alanine as a precursor for hepatic gluconeogenesis in humans.Summarizing all the data and discussions presented in this paper together with those in the preceding one (7Xue H.-H. Fujie M. Sakaguchi T. Oda T. Ogawa H. Kneer N.M. Lardy H.A. Ichiyama A. J. Biol. Chem. 1999; 274: 16020-16027Abstract Full Text Full Text PDF PubMed Scopus (38) Google Scholar), we believe that SDH, SPT/AGT, cSHMT, mSHMT, and GCS work as schematically shown in Fig. 3 in the hepatic metabolism ofl-serine and glycine in rats, rabbits, humans, and dogs. In this study, we have presented in vitro and in vivo data suggesting that, in rabbit, dog, and human livers, SPT/AGT substantially contributes to the metabolism ofl-serine, whereas the contribution of SDH is fairly small. This pattern of l-serine metabolism is in contrast to the observation that in rat liver the contribution of SDH is the largest, and the flux through SPT/AGT accounts for only traces unless this enzyme has been induced by a previous administration of glucagon (7Xue H.-H. Fujie M. Sakaguchi T. Oda T. Ogawa H. Kneer N.M. Lardy H.A. Ichiyama A. J. Biol. Chem. 1999; 274: 16020-16027Abstract Full Text Full Text PDF PubMed Scopus (38) Google Scholar). Such species-specific patterns of the l-serine metabolism approximately agree with the observed activities of serine-metabolizing enzymes in respective animals (Table I). Our results are compatible with the observation by Rowsell et al. (8Rowsell E.V. Carnie J.A. Wahbi S.D. Al-Tai A.H. Rowsell K.V. Comp. Biochem. Physiol. 1979; 63B: 543-555Google Scholar) that in rabbit and dog livers the SPT/AGT activity is more than six times higher, and the SDH activity is much lower than the respective activities in rat liver. It is noteworthy that SPT/AGT is involved in the l-serine metabolism, no matter whether the enzyme is largely located in mitochondria (dog liver) or entirely in peroxisomes (rabbit and human livers). It has been expected that mitochondrial SPT/AGT plays a role in l-serine metabolism, because in the rat, the flux through SPT/AGT in gluconeogenesis from l-serine was apparent only when liver mitochondrial SPT/AGT had been induced by glucagon (7Xue H.-H. Fujie M. Sakaguchi T. Oda T. Ogawa H. Kneer N.M. Lardy H.A. Ichiyama A. J. Biol. Chem. 1999; 274: 16020-16027Abstract Full Text Full Text PDF PubMed Scopus (38) Google Scholar). This was corroborated in the present study by demonstrating in in vitro experiments under quasi-physiological conditions that the flux through SPT/AGT accounts for a large portion of l-serine metabolized in dog liver. These results are in accordance with the observation of Beliveau and Freedland (17Beliveau G.P. Freedland R.A. Comp. Biochem. Physiol. 1982; 71B: 13-18Google Scholar) that serine is mainly metabolized via transamination in hepatocytes isolated from the cat, another carnivore. As for the peroxisomal SPT/AGT, on the other hand, an important role in the conversion of glyoxylate to glycine has been indicated from the studies on primary hyperoxaluria type 1 (6Danpure C.J. Purdue P.E. Scriver C.R. Beaudet A.L. Sly W.S. Valle D. 7th Ed. The Metabolic and Molecular Bases of Inherited Disease. 2. McGraw-Hill, New York1995: 2385-2424Google Scholar). In the present study, the peroxisomal SPT/AGT was also shown to participate inl-serine metabolism in vitro (Table II). In addition, in the case of rabbit liver, an infusion experiment withl-[3-3H,14C]serine suggested that the flux through SPT/AGT contributes to gluconeogenesis froml-serine in vivo and accounts for as much as ∼90% of it (Table III). It is evident that peroxisomal SPT/AGT plays dual roles in the metabolism of serine and glyoxylate. It is possible, although it has not yet been experimentally proved, that mitochondrial SPT/AGT also plays a role in the metabolism of glyoxylate.l-Hydroxyproline has been shown to be metabolized to glyoxylate in mitochondria (or peroxisomes, 18,000 × gprecipitate; Ref. 18Maitra U. Pekker E.E. J. Biol. Chem. 1964; 237: 1485-1491Google Scholar), and glyoxylate thus formed was proposed to be converted to glycine by mitochondrial SPT/AGT, although the quantities of the hydroxyproline-derived glyoxylate must be small (1Snell K. Adv. Enzyme Regul. 1984; 22: 325-400Crossref PubMed Scopus (224) Google Scholar, 19Rowsell E.V. Snell K. Carnie J.A. Rowsell K.V. Biochem. J. 1972; 127: 155-165Crossref PubMed Scopus (44) Google Scholar). SPT/AGT is thus a unique enzyme of dual organelle localization, and it is possible that the enzyme in either organelle plays dual roles, gluconeogenesis from serine and conversion of glyoxylate to glycine by transamination. Such dual functions probably come from the fact that serine:glyoxylate aminotransferase (EC 2.6.1.45), the plant counterpart of animal SPT/AGT (EC 2.6.1.44/2.6.1.51), catalyzes transamination between serine and glyoxylate in the photorespiratory nitrogen cycle (20Keys A.J. Bird I.F. Cornelius M.J. Lea P.J. Wallsgrove R.M. Miflin B.J. Nature. 1978; 275: 741-743Crossref Scopus (328) Google Scholar), forming hydroxypyruvate and glycine, the latter being converted back to serine by a mitochondrial enzyme system. It is unlikely that glyoxylate is supplied in the animal livers as abundantly as in the photorespiration in plant leaves. Therefore, the hepatic serine metabolism catalyzed by SPT/AGT may not be necessarily coupled with the glyoxylate-to-glycine conversion, and more versatile pyruvate may also be used as an amino acceptor from serine, although the affinity of the enzyme for glyoxylate is much higher than that for pyruvate, as demonstrated by much lower K m for glyoxylate (10 μm) than that for pyruvate (480 μm) of the rat liver enzyme at pH 7.4 (21Yanagisawa M. Higashi S. Oda T. Ichiyama A. Lennone D.F. Stratman F.W. Zahtten R.N. Biochemistry of Metabolic Processes. Elsevier, Amsterdam1983: 413-426Google Scholar). Because plant tissues contain significant amounts of glycolate (22Harris K.S. Richardson K.E. Invest. Urol. 1980; 18: 106-109PubMed Google Scholar), and the conversion of glycolate to glyoxylate takes place in liver peroxisomes, the peroxisomal location of SPT/AGT may be favorable for herbivores to convert the glycolate-derived glyoxylate to glycine and to prevent harmful overproduction of oxalate. For carnivores, on the other hand, there may be less need of the peroxisomal location of SPT/AGT, because meats contain much less glycolate (22Harris K.S. Richardson K.E. Invest. Urol. 1980; 18: 106-109PubMed Google Scholar). With respect to its role in the disposal of serine demonstrated in this study, SPT/AGT in either of the two organelles appears to function with similar efficiency. Thus the necessity and advantages to carnivores of having SPT/AGT in mitochondria are not yet fully understood and need further studies. As for the metabolism of l-serine via glycine, the overall flux observed with reconstituted cytoplasmic extracts from rabbit, human, and dog livers was similar to that in the case of rat liver. As proposed in the preceding paper (7Xue H.-H. Fujie M. Sakaguchi T. Oda T. Ogawa H. Kneer N.M. Lardy H.A. Ichiyama A. J. Biol. Chem. 1999; 274: 16020-16027Abstract Full Text Full Text PDF PubMed Scopus (38) Google Scholar), the SHMT-catalyzed interconversion between serine and glycine may contribute, at least in part, to the maintaining of their intracellular concentration balance, in response to supply or use of these amino acids and tetrahydrofolate coenzymes, and the degradation of glycine by GCS may be considered as a metabolic exit of not only glycine but also l-serine. This view was further supported in the present study by showing that, irrespective of the animal species tested, the conversion of serine to glycine catalyzed by cSHMT occurred fairly rapidly, followed by the GCS-mediated slow decarboxylation of the accumulated glycine. However, the flux through GCS as well as that through SDH and SPT/AGT varied considerably from animal to animal. In dog liver in which the activity of GCS was relatively high, the contribution of the flux through GCS was comparable with that through SPT/AGT, but in rabbit and human livers the GCS pathway accounted for only a small portion ofl-serine metabolized (Table II). It has been previously noted that the activity of GCS is relatively small, and the apparent low activity may have some rationale, because glycine is an important amino acid that is used in many ways in the cells (12Kikuchi G. Mol. Cell. Biochem. 1973; 1: 169-187Crossref PubMed Scopus (252) Google Scholar). Although the flux through SPT/AGT is one of the major metabolic exits of serine in rabbit, human, and dog livers, its activity is also relatively small, consistent with the previous observation by Felig et al.(23Felig P. Owen O.E. Wahren J. Cahill Jr., G.F. J. Clin. Invest. 1969; 48: 584-593Crossref PubMed Scopus (481) Google Scholar) that serine, as well as glycine, is less effective than alanine as a precursor for hepatic gluconeogenesis in humans. Summarizing all the data and discussions presented in this paper together with those in the preceding one (7Xue H.-H. Fujie M. Sakaguchi T. Oda T. Ogawa H. Kneer N.M. Lardy H.A. Ichiyama A. J. Biol. Chem. 1999; 274: 16020-16027Abstract Full Text Full Text PDF PubMed Scopus (38) Google Scholar), we believe that SDH, SPT/AGT, cSHMT, mSHMT, and GCS work as schematically shown in Fig. 3 in the hepatic metabolism ofl-serine and glycine in rats, rabbits, humans, and dogs. We are indebted to Prof. Satoshi Nakamura (Second Department of Surgery, Hamamatsu University School of Medicine) and Dr. Kazuya Suzuki (First Department of Surgery, Hamamatsu University School of Medicine) for their kind supply of human and dog liver specimens, respectively." @default.
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W1991782016 title "Flux of the l-Serine Metabolism in Rabbit, Human, and Dog Livers" @default.
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