Structure of a CBS-domain pair from the regulatory γ1 subunit of human AMPK in complex with AMP and ZMP

Day, Philip M; Sharff, A.; Parra, Lina; Cleasby, Anne; Williams, Mark W.; Hörer, Stefan; Nar, Herbert; Redemann, Norbert; Tickle, Ian J.; Yon, Jeannine

doi:10.1107/s0907444907009110

Cited by 82 publications

(101 citation statements)

References 53 publications

(55 reference statements)

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“…1B). AMPK, for example, which is required for certain methods of diet restriction to increase Caenorhabditis elegans lifespan, contains two pairs of CBS domains that bind AMP directly to mediate its activity (19,20). We therefore investigated whether dCBS activity was affected by changes in the ATP/AMP ratio.…”

Section: Resultsmentioning

confidence: 99%

Increased transsulfuration mediates longevity and dietary restriction in Drosophila

Kabil

Banerjee

et al. 2011

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

128

154

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The mechanisms through which dietary restriction enhances health and longevity in diverse species are unclear. The transsulfuration pathway (TSP) is a highly conserved mechanism for metabolizing the sulfur-containing amino acids, methionine and cysteine. Here we show that Drosophila cystathionine β-synthase (dCBS), which catalyzes the rate-determining step in the TSP, is a positive regulator of lifespan in Drosophila and that the pathway is required for the effects of diet restriction on animal physiology and lifespan. dCBS activity was up-regulated in flies exposed to reduced nutrient conditions, and ubiquitous or neuron-specific transgenic overexpression of dCBS enhanced longevity in fully fed animals. Inhibition of the TSP abrogated the changes in lifespan, adiposity, and protein content that normally accompany diet restriction. RNAi-mediated knockdown of dCBS also limited lifespan extension by diet. Diet restriction reduced levels of protein translation in Drosophila, and we show that this is largely caused by increased metabolic commitment of methionine cycle intermediates to transsulfuration. However, dietary supplementation of methionine restored normal levels of protein synthesis to restricted animals without affecting lifespan, indicating that global reductions in translation alone are not required for diet-restriction longevity. Our results indicate a mechanism by which dietary restriction influences physiology and aging.hydrogen sulfide | essential amino acids | metabolism | healthspan F or a broad range of taxonomically diverse organisms, the quality of their diet acts as a powerful modulator of health and longevity through molecular mechanisms that are largely unknown. Lifespan is extended, for example, when food is restricted to an extent that falls short of inducing starvation. In mammals, this manipulation, which is often called dietary restriction (DR), not only increases lifespan but also imparts a broad-spectrum improvement in health during aging. In humans, for example, DR reduces risk factors for diabetes, cardiovascular disease, and cancer (1).Transsulfuration is an evolutionarily ancient metabolic process that involves a network of enzymes responsible for the metabolism of sulfur-containing amino acids. The transsulfuration pathway (TSP) has been studied extensively in mammals, in which it has been shown to direct the conversion of homocysteine to cysteine following the breakdown of methionine, an essential amino acid. Flux through the TSP is known to affect overall cellular metabolism by directly influencing cysteine and methionine levels. Methionine availability affects protein synthesis and methylation, and it has been implicated in murine aging (2). Cysteine availability controls the synthesis of glutathione (GSH), which is the chief regulator of cellular redox homeostasis and an important agent in xenobiotic detoxification (Fig. 1A). Patients with genetic defects in the TSP are characterized by high levels of homocysteine, low levels of GSH, and increased incidence of age-related path...

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Section: Resultsmentioning

confidence: 99%

Increased transsulfuration mediates longevity and dietary restriction in Drosophila

Kabil

Banerjee

et al. 2011

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

128

154

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“…For instance, in liver, SIRT1 activates AMPK activity and reduces expression of fas, leading to diminished lipid accumulation ( 46,47 ). On the other conversion into ZMP, an AMP mimetic ( 55 ). On the other hand, several antidiabetic drugs, including thiazolidinediones, metformin, and berberine, activate AMPK by changing mitochondrial activity ( 45,(56)(57)(58).…”

Section: Glabridin Affects Mitochondrial Functions and Cellular Amp/amentioning

confidence: 99%

AMPK activation with glabridin ameliorates adiposity and lipid dysregulation in obesity

Lee

Choe

Jang

et al. 2012

Journal of Lipid Research

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Obesity is characterized by excessive accumulation of lipid metabolites in adipose tissues as well as in nonadipose tissues, such as liver, muscle, and pancreas ( 1 ). Because obesity is considered as a major risk factor for most metabolic diseases, including hyperlipidemia, hypercholesterolemia, type 2 diabetes, hypertension, and cardiovascular disease ( 2-4 ), numerous investigations have been conducted to elucidate the key components in energy homeostasis, which is crucial to develop therapeutic agents for obesity and obesity-associated metabolic disorders.AMP-activated protein kinase (AMPK) is a master energy sensor that integrates nutrients, hormones, and stress signals to maintain whole-body energy homeostasis ( 5, 6 ). Under various stress conditions, AMPK is activated by allosteric stimulation in response to an increased AMP/ATP ratio or mitochondria activity change. AMPK activation also is induced by upstream stress kinases, such as liver kinase B1 (LKB1) or calcium/calmodulin-dependent protein kinase kinase (CaMKK) ( 7-10 ). Activated AMPK is involved in the regulation of diverse metabolic pathways.

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“…At higher concentrations, AICAR is a potent low energy mimetic that stimulates AMP-activated protein kinase (AMPK) by mimicking activation by AMP (2,3). In vivo, this AMPK activating effect was shown to increase the endurance of sedentary mice (4).…”

Section: Amino-imidazole Carboxamide Ribonucleotide Monophosphate (Aimentioning

confidence: 99%

Identification of Yeast and Human 5-Aminoimidazole-4-carboxamide-1-β-d-ribofuranoside (AICAr) Transporters

Ceschin

Saint-Marc

Laporte

et al. 2014

Journal of Biological Chemistry

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Structure of a CBS-domain pair from the regulatory γ1 subunit of human AMPK in complex with AMP and ZMP

Cited by 82 publications

References 53 publications

Increased transsulfuration mediates longevity and dietary restriction in Drosophila

Increased transsulfuration mediates longevity and dietary restriction in Drosophila

AMPK activation with glabridin ameliorates adiposity and lipid dysregulation in obesity

Identification of Yeast and Human 5-Aminoimidazole-4-carboxamide-1-β-d-ribofuranoside (AICAr) Transporters

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