Lysine α-ketoglutarate reductase, but not saccharopine dehydrogenase, is subject to substrate inhibition in pig liver

Pink, Desmond; Gatrell, Stephanie; Elango, Rajavel; Turchinsky, Joan; Kiess, Aaron S.; Blemings, Kenneth P.; Dixon, Walter T.; Ball, Ronald O.

doi:10.1016/j.nutres.2011.06.001

Cited by 20 publications

(13 citation statements)

References 44 publications

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“…Most of the catabolic process occurs in the liver through the saccharopine α-aminoadipate d-semialdehyde pathway. However, a great capacity for Lys degradation through the same pathway has been also discovered in non-hepatic tissues, such as intestine and muscle 22,23 . The two key enzymes of the pathway, lysine α-ketoglutarate reductase (LKR) and saccharopine dehydrogenase (SDH), are catalyzed by the bifunctional protein aminoadipate-semialdehyde synthase (AASS) 24 .A genome wide association study conducted by Fontanesi et al .…”

Section: Introductionmentioning

confidence: 99%

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Dose-response of different dietary leucine levels on growth performance and amino acid metabolism in piglets differing for aminoadipate-semialdehyde synthase genotypes

Bertocchi

Bosi

Luise

et al. 2019

Sci Rep

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Dose-response studies of dietary leucine (Leu) in weaners are needed for a proper diet formulation. Dietary Leu effect was assessed in a 3-weeks dose-response trial with a 2 (genotype) x 5 (diets) factorial arrangement on one-hundred weaned pigs (9 to 20 kg body weight (BW)). Pigs differed for a polymorphism at the aminoadipate-semialdehyde synthase (AASS) gene, involved in lysine (Lys) metabolism. Pigs received experimental diets (d7 to d28) differing for the standardized ileal digestible (SID) Leu:Lys: 70%, 85%, 100%, 115%, 130%. Daily feed intake (ADFI), daily gain (ADG) and feed:gain (F:G) in all pigs and ADG and F:G in two classes of BW were analyzed using regression analysis with curvilinear-plateau (CLP) and linear quadratic function (LQ) models. Amino acid (AA) concentrations in plasma, liver, muscle and urine were determined. AASS genotype did not affect the parameters. Dietary Leu affected performance parameters, with a maximum response for ADG and F:G between 100.5% and 110.7% SID Leu:Lys, higher than the usually recommended one, and between 110.5% and 115.4% and between 94.9% and 110.2% SID Leu:Lys for ADG for light and heavy pigs respectively. AA variations in tissues highlighted Leu role in protein synthesis and its influence on the other branched chain AAs.

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Section: Introductionmentioning

confidence: 99%

“…Moreover, this degradation mainly depends on the bifunctional protein AASS . Therefore, modification or inhibition of the functions of this enzyme could reduce Lys degradation, directing this AA towards protein synthesis and reducing its requirement 23,24 .…”

Section: Introductionmentioning

confidence: 99%

Dose-response of different dietary leucine levels on growth performance and amino acid metabolism in piglets differing for aminoadipate-semialdehyde synthase genotypes

Bertocchi

Bosi

Luise

et al. 2019

Sci Rep

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“…Tissue-specific responses to Lys supply have been shown to alter AASS activity and abundance in several species (Cleveland et al, 2008;Pink et al, 2011). The lack of response of AASS abundance to postruminal infusion of Lys when matched with increasing plasma α-aminoadipic acid in the present study suggests alternative metabolism of Lys or adequate basal Lys catabolism that lacks induction when Lys is supplied up to requirement in lactating dairy cows.…”

Section: Discussionmentioning

confidence: 54%

Hepatic expression of aminoadipate semialdehyde synthase is unchanged by postruminal lysine supply in lactating dairy cows

Tucker

Hanigan

Escobar³

et al. 2017

Journal of Dairy Science

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Lysine supply is potentially limiting for milk production in dairy cows. The availability of Lys to the mammary gland and other tissues is a function of the quantity of metabolizable Lys supplied and Lys catabolism by the liver. Likewise, Lys catabolism may be influenced by Lys supply. This study evaluated the effect of increased postruminal Lys supply on the expression of aminoadipate semialdehyde synthase (AASS, a committing step in Lys catabolism in the liver) and ornithine transcarbamoylase and argininosuccinate synthase (key urea cycle enzymes that are responsive to protein supply). Eight multiparous peak Holstein cows were used in a replicated 4 × 4 Latin square. Cows were fed a Lys-limiting ration and infused postruminally with 0, 9, 27, or 63 g/d of Lys. The study consisted of 10 d of pretreatment followed by 10 d of Lys infusion. On the last day of each period, liver and milk samples were collected for mRNA analysis, and blood samples were collected for analysis of amino acids and Lys metabolites. Milk protein percent increased by 5.9%, plasma Lys increased by 74%, and α-aminoadipic acid increased by 51% with postruminal infusion of 63 g/d Lys compared with 0 g/d. Expression of AASS, ornithine transcarbamoylase, and argininosuccinate synthase mRNA in liver did not differ with postruminal infusion of Lys. Milk fat globule mRNA for major milk proteins and AASS were not affected by Lys infusion. Postruminal infusion of Lys resulted in an 86% greater increase in AASS mRNA in the liver compared with mammary mRNA. These changes suggest that hepatic Lys metabolism is not responsive to Lys supply at the transcription level, and that the availability of Lys to extrahepatic tissue may be determined by hepatic Lys metabolism.

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“…6L). The oxidation of lysine in mitochondria can be used as an alternative source of NADH and FADH 2 via the enzymes saccharopine dehydrogenase [24], and glutaryl CoA dehydrogenase, respectively.…”

Section: Resultsmentioning

confidence: 99%

A Mutation in the Mitochondrial Aspartate/Glutamate Carrier Leads to a More Oxidizing Intramitochondrial Environment and an Inflammatory Myopathy in Dutch Shepherd Dogs

Shelton

Minor

et al. 2019

JND

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Background:Inflammatory myopathies are characterized by infiltration of inflammatory cells into muscle. Typically, immune-mediated disorders such as polymyositis, dermatomyositis and inclusion body myositis are diagnosed.Objective:A small family of dogs with early onset muscle weakness and inflammatory muscle biopsies were investigated for an underlying genetic cause.Methods:Following the histopathological diagnosis of inflammatory myopathy, mutational analysis including whole genome sequencing, functional transport studies of the mutated and wild-type proteins, and metabolomic analysis were performed.Results:Whole genome resequencing identified a pathological variant in the SLC25A12 gene, resulting in a leucine to proline substitution at amino acid 349 in the mitochondrial aspartate-glutamate transporter known as the neuron and muscle specific aspartate glutamate carrier 1 (AGC1). Functionally reconstituting recombinant wild-type and mutant AGC1 into liposomes demonstrated a dramatic decrease in AGC1 transport activity and inability to transfer reducing equivalents from the cytosol into mitochondria. Targeted, broad-spectrum metabolomic analysis from affected and control muscles demonstrated a proinflammatory milieu and strong support for oxidative stress.Conclusions:This study provides the first description of a metabolic mechanism in which ablated mitochondrial glutamate transport markedly reduced the import of reducing equivalents into mitochondria and produced a highly oxidizing and proinflammatory muscle environment and an inflammatory myopathy.

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Lysine α-ketoglutarate reductase, but not saccharopine dehydrogenase, is subject to substrate inhibition in pig liver

Cited by 20 publications

References 44 publications

Dose-response of different dietary leucine levels on growth performance and amino acid metabolism in piglets differing for aminoadipate-semialdehyde synthase genotypes

Dose-response of different dietary leucine levels on growth performance and amino acid metabolism in piglets differing for aminoadipate-semialdehyde synthase genotypes

Hepatic expression of aminoadipate semialdehyde synthase is unchanged by postruminal lysine supply in lactating dairy cows

A Mutation in the Mitochondrial Aspartate/Glutamate Carrier Leads to a More Oxidizing Intramitochondrial Environment and an Inflammatory Myopathy in Dutch Shepherd Dogs

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