Lysine metabolism in mammals

The metabolism of dietary essential amino acids by the gut has a direct effect on their systemic availability and potentially limits growth. We demonstrate that, in neonatal pigs bearing portal and arterial catheters and fed a diet containing 23% protein [high protein (HP) diet], more than half the intake of essential amino acids is metabolized by the portal-drained viscera (PDV). Intraduodenal or i.v. infusions of [U-13 C]-lysine were used to measure the appearance across and the use of the tracer by the PDV. In HP-fed pigs, lysine use by the PDV was derived almost entirely from the arterial input. In these animals, the small amount of dietary lysine used in first pass was oxidized almost entirely. Even so, intestinal lysine oxidation (24 mol͞kg per h) accounted for one-third of whole-body lysine oxidation (77 mol͞kg per h). Total lysine use by the PDV was not affected by low protein (LP) feeding (HP, 213 mol͞kg per h; LP,186 mol͞kg per h). In LP-fed pigs, the use of lysine by the PDV accounted for more than 75% of its intake. In contrast to HP feeding, both dietary and arterial lysines were used by the PDV of LP-fed pigs in nearly equal amounts. Intestinal lysine oxidation was suppressed completely. We conclude that the PDV are key organs with respect to amino acid metabolism and that the intestines use a disproportionately large amount of the dietary supply of amino acids during protein restriction.T he portal-drained viscera (PDV; the intestines, pancreas, spleen, and stomach) contribute between 20% and 35% of whole-body energy expenditure and protein synthesis, even though they contribute less than 6% of body weight (1-3). Dietary amino acid use by the intestine could have a substantial effect on their systemic availability and thereby regulate wholebody protein deposition. Studies in a number of mammalian species show that dietary essential amino acids (EAA) are directly used by the intestines for protein synthesis and other biosynthetic pathways (4-6).Futhermore, under high protein (HP) feeding conditions, intestinal energy production is derived largely from the oxidation of glutamate, glutamine, and aspartate (7-9). However, the oxidation of these substrates accounts for neither the total CO 2 production nor the production of alanine and ammonia by the PDV. The failure to account for the nitrogen outflow from the metabolism of glutamate, glutamine, and aspartate has led us to conclude that other amino acids, possibly including EAA, are oxidized in the PDV. There is evidence that leucine and methionine are oxidized by the enterocytes (10, 11), but we know of no detailed in vivo investigations of intestinal catabolism of other EAA. In this context, the oxidation of lysine would be of particular consequence, because this amino acid is nutritionally first limiting in cereal-based diets and milk (12).Investigations carried out 25 years ago were unable to find evidence for the presence of enzymes required for lysine catabolism in enterocytes (13,14), and it is generally held that lysine catabolism occurs prima...

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“…6 ϫ 6 ϫ Eq. 1, [15] where the denominator is multiplied by a factor of 6 to account for the six carbon atoms that are labeled in the tracer.…”

Section: [11]mentioning

confidence: 99%

“…Investigations carried out 25 years ago were unable to find evidence for the presence of enzymes required for lysine catabolism in enterocytes (13,14), and it is generally held that lysine catabolism occurs primarily in the liver (15)(16)(17). Whether lysine is catabolized by the intact intestine in vivo has not been investigated.…”

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confidence: 99%

Adaptive regulation of intestinal lysine metabolism

Goudoever

Stoll

Henry

et al. 2000

Proc. Natl. Acad. Sci. U.S.A.

136

102

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“…This pathway has been described in plants [1][2][3][4] and mammals [5][6][7][8][9][10], and its first two reactions are catalysed by enzymic activities known as lysine-oxoglutarate reductase (LOR ; EC 1.5.1.8) and saccharopine dehydrogenase (SDH ; EC 1.5.1.9). The reductase activity condenses lysine and 2-oxoglutarate to form saccharopine [ε-N-(-glutaryl-2)--lysine].…”

Section: Introductionmentioning

confidence: 99%

“…In mammals, the saccharopine pathway is important for lysine catabolism in the liver, and it involves LOR and SDH activities that are biochemically similar to those described in plants [6][7][8][9][10]14]. In baboon and bovine livers these two activities reside on a single polypeptide [14,15] and the bifunctional protein purified from these sources has been named aminoadipic semiAbbreviations used : LOR, lysine-oxoglutarate reductase ; PEG, poly(ethylene glycol) ; SDH, saccharopine dehydrogenase.…”

Section: Introductionmentioning

confidence: 99%

Lysine degradation through the saccharopine pathway in mammals: involvement of both bifunctional and monofunctional lysine-degrading enzymes in mouse

Papes

Kemper

Cord-Neto

et al. 1999

Biochemical Journal

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Lysine-oxoglutarate reductase and saccharopine dehydrogenase are enzymic activities that catalyse the first two steps of lysine degradation through the saccharopine pathway in upper eukaryotes. This paper describes the isolation and characterization of a cDNA clone encoding a bifunctional enzyme bearing domains corresponding to these two enzymic activities. We partly purified those activities from mouse liver and showed for the first time that both a bifunctional lysine-oxoglutarate reductase/saccharopine dehydrogenase and a monofunctional saccharopine dehydrogenase are likely to be present in this organ. Northern analyses indicate the existence of two mRNA species in liver and kidney. The longest molecule, 3.4 kb in size, corresponds to the isolated cDNA and encodes the bifunctional enzyme. The 2.4 kb short transcript probably codes for the monofunctional dehydrogenase. Sequence analyses show that the bifunctional enzyme is likely to be a mitochondrial protein. Furthermore, enzymic and expression analyses suggest that lysine-oxoglutarate reductase/saccharopine dehydrogenase levels increase in livers of mice under starvation. Lysine-injected mice also show an increase in lysine-oxoglutarate reductase and saccharopine dehydrogenase levels.

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“…lysine + a-ketoglutarate + NADPH -* saccharopine + NADP+ The enzyme has been characterized in human and animal tissues (3,7,8) where it is believed to catalyze the first step of lysine catabolism (4). A similar reaction involving NAD is catalyzed by saccharopine dehydrogenase, an enzyme found in yeast and fungi where the reverse of the above reaction is considered to be the final step of lysine biosynthesis (5,6,12,16).…”

mentioning

confidence: 99%

Lysine-Ketoglutarate Reductase Activity in Developing Maize Endosperm

Arruda¹,

Sodek²,

Silva³

1982

Plant Physiol.

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Lysine-ketoglutarate reductase activity was detected and characterzed in the developing endosperm of maize (Zea mays L). The enzyme showed specificity for its substrates: lysine, a-ketoglutarate, and NADPH. Formation of the reaction product saccharopine was demonstrated. The pH optimum of the enzyme was cdose to 7, and the Km for lysine and aketoglutarate were 5.2 and 1.8 millmolar, respectively. between 25 and 70%o saturation was collected and taken up in 2.5 ml of extraction buffer. After desalting on a Sephadex G-25 column (1.5 x 16 cm), the protein fraction was assayed for lysineketoglutarate reductase activity using conditions based on those described by Hutzler and Dancis (7). The assay mixture contained K-phosphate (pH 7.0; 300 ,umol), L-lysine (50 ,pmol), a-ketoglutarate (25 ,umol), NADPH (300 nmol), and enzyme (0.1-0.2 mg protein) in a total volume of 3 ml. The mixture was incubated at 30°C, and oxidation of NADPH was monitored in a spectrophotometer at 340 nm.Lysine-ketoglutarate reductase catalyzes the following reaction: lysine + a-ketoglutarate + NADPH -* saccharopine + NADP+ The enzyme has been characterized in human and animal tissues (3,7,8) where it is believed to catalyze the first step of lysine catabolism (4). A similar reaction involving NAD is catalyzed by saccharopine dehydrogenase, an enzyme found in yeast and fungi where the reverse of the above reaction is considered to be the final step of lysine biosynthesis (5,6,12,16). Thus, in some organisms saccharopine is an intermediate of lysine biosynthesis while in the others it appears to be involved in lysine breakdown. Actually, several pathways for lysine catabolism are known (11), but in higher plants no general pathway has been established. Nevertheless, tracer studies with barley seedlings have provided strong evidence for the pathway involving saccharopine as intermediate (10), suggesting that this route may be important for lysine breakdown in cereals at least. However, we are unaware of any studies with enzymes in higher plants in support of this pathway.In this report, we describe the characterization of lysine-ketoglutarate reductase in developing maize endosperm, a tissue known to degrade lysine extensively (14). MATERIALS AND METHODS RESULTS AND DISCUSSIONThe data in Table I show that partially purified extracts of maize endosperm oxidized NADPH in the presence of lysine and a-ketoglutarate. In the absence of one or both of these substrates, the oxidation of NADPH was minimal. Specificity for the substrates is indicated by the fact that several amino acids, including closely related structures such as L-ornithine and D-lysine, would not substitute for L-lysine, nor would oxaloacetate or pyruvate substitute for a-ketoglutarate. NADH would not replace NADPH as electron donor, as was found for the enzyme from human liver (7).To confirm that the activity being measured was truly lysineketoglutarate reductase, it would be essential to demonstrate the formation of saccharopine in the assay. This was attempted using I4CJlysine...

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Lysine metabolism in mammals

Cited by 51 publications

References 13 publications

Adaptive regulation of intestinal lysine metabolism

Adaptive regulation of intestinal lysine metabolism

Lysine degradation through the saccharopine pathway in mammals: involvement of both bifunctional and monofunctional lysine-degrading enzymes in mouse

Lysine-Ketoglutarate Reductase Activity in Developing Maize Endosperm

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