Multiple Enzyme Defects in Familial Hyperlysinemia

Dancis, Joseph; Hutzler, Joel; Woody, Norman C.; Cox, Rody P.

doi:10.1203/00006450-197607000-00011

Cited by 35 publications

(20 citation statements)

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“…SDH from human placenta has an M , of 480,000 and could not be separated from LKR, suggesting that both activities are present in the same polypeptide (Fjellstedt and Robinson, 197513). However, genetic diseases that independently affect the accumulation of Lys and saccharopine because of deficiencies in the activities of LKR and SDH, respectively, suggested the existence of two genes encoding the two enzymes (Hutzler and Dancis, 1970;Dancis et al, 1976). The purification to apparent homogeneity of both LKR and SDH from baboon and bovine livers provided direct evidence that the two enzyme activities reside in a single polypeptide of 115 kD (Markovitz et al;1984).…”

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Purification and Characterization of the Bifunctional Enzyme Lysine-Ketoglutarate Reductase-Saccharopine Dehydrogenase from Maize

et al. 1996

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l h e first enzyme of the lysine degradation pathway in maize (Zea mays L.), lysine-ketoglutarate reductase, condenses lysine and a-ketoglutarate into saccharopine using NADPH as a cofactor, whereas the second, saccharopine dehydrogenase, converts saccharopine to a-aminoadipic-6-semialdehyde and glutamic acid using NAD+ or NADP+ as a cofactor. l h e reductase and dehydrogenase activities are optimal at pH 7.0 and 9.0, respectively. Both enzyme activities, co-purified on diethylaminoethyl-cellulose and gel filtration columns, were detected on nondenaturing polyacrylamide gels as single bands with identical electrophoretic mobilities and share tissue specificity for the endosperm. l h e highly purified preparation containing the reductase and dehydrogenase activities showed a single polypeptide band of 125 kD on sodium dodecyl sulfate-polyacrylamide gel electrophoresis. The native form of the enzyme is a dimer of 260 kD. Limited proteolysis with elastase indicated that lysineketoglutarate reductase and saccharopine dehydrogenase from maize endosperm are located in two functionally independent domains of a bifunctional polypeptide.

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Purification and Characterization of the Bifunctional Enzyme Lysine-Ketoglutarate Reductase-Saccharopine Dehydrogenase from Maize

et al. 1996

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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].…”

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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%

“…This opens the question of whether the degradation of lysine has any functional significance during brain development and puts a new focus on the nutritional requirements for lysine in gestation and infancy. Fourthly, LOR and\or SDH deficiencies seem to be involved in a human autosomic genetic disorder known as familial hyperlysinaemia, which is characterized by serious defects in the functioning of the nervous system [10,24,25].…”

Section: Introductionmentioning

confidence: 99%

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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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“…Formerly it had been thought that such catabolism proceeded via a circuitous route involving pipecolic acid (Figure 1). Compelling evidence that the major route of lysine breakdown in the human is via saccharopine came from the discovery of genetic diseases in infants with impairments in saccharopine formation (reverse Reaction 2) or degradation (reverse Reaction 1), resulting in hyperlysinemia (11). Lysine catabolism in animals involves, then, a reversal of the fungal biosynthetic pathway to ketoadipate ( Figure 1) and subsequent breakdown to CO 2 and H 2 O.…”

Section: Life In a College Of Agriculture University Of Illinois 19mentioning

confidence: 99%

Memories of Microbesand Metabolism

Broquist

1997

Annu. Rev. Nutr.

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As Jackie Gleason was wont to say: "How sweet it really is!" And-reflecting on the 1940s-1980s, when studies of microbial nutrition revealed exciting structurefunction relationships of the B-complex vitamins with relevance to metabolism in humans-it really is. A chemistry degree from Beloit College and a doctorate in biochemistry from the University of Wisconsin set the stage for my life's work at Lederle Laboratories, the University of Illinois, and Vanderbilt University. At Lederle my research contributed to folic acid chemistry: coenzyme forms and function; antimetabolites and cancer chemotherapy. My subsequent university studies centered on lysine biosynthesis and metabolism, e.g. its precursor role in carnitine and in indolizidine alkaloids of physiological interest. There were also many opportunities to reach out and give something back to the system via teaching and diverse service activities, all of which has led to a happy, fulfilling career, one for which I am ever thankful. CONTENTS

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Multiple Enzyme Defects in Familial Hyperlysinemia

Cited by 35 publications

References 7 publications

Purification and Characterization of the Bifunctional Enzyme Lysine-Ketoglutarate Reductase-Saccharopine Dehydrogenase from Maize

Purification and Characterization of the Bifunctional Enzyme Lysine-Ketoglutarate Reductase-Saccharopine Dehydrogenase from Maize

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

Memories of Microbesand Metabolism

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