Regulation of purine de novo synthesis in cultured human fibroblasts: The role of

The current molecular understanding of Alzheimer’s disease (AD) has still not resulted in successful interventions. Mitochondrial dysfunction of the AD brain is currently emerging as a hallmark of this disease. One mitochondrial function often affected in AD is oxidative phosphorylation responsible for ATP production, but also for production of reactive oxygen species (ROS) and for the de novo synthesis of pyrimidines. This paper reviews the role of mitochondrial produced ROS and pyrimidines in the aetiology of AD and their proposed role in oxidative degeneration of macromolecules, synthesis of essential phospholipids and maintenance of mitochondrial viability in the AD brain.

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The role of particulate carbon in the de-novo synthesis of polychlorinated dibenzodioxins and-furans in fly-ash

Chemosphere ◽

10.1016/0045-6535(90)90365-z ◽

1990 ◽

Vol 20 (10-12) ◽

pp. 1953-1958 ◽

Cited By ~ 39

Author(s):

L. Stieglitz ◽

G. Zwick ◽

J. Beck ◽

H. Bautz ◽

W. Roth

Keyword(s):

Fly Ash ◽

De Novo ◽

De Novo Synthesis ◽

Particulate Carbon ◽

Polychlorinated Dibenzodioxins

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NAD+-Dependent Deacetylase Hst1p Controls Biosynthesis and Cellular NAD+ Levels in Saccharomyces cerevisiae

Molecular and Cellular Biology ◽

10.1128/mcb.23.19.7044-7054.2003 ◽

2003 ◽

Vol 23 (19) ◽

pp. 7044-7054 ◽

Cited By ~ 97

Author(s):

Antonio Bedalov ◽

Maki Hirao ◽

Jeffrey Posakony ◽

Melisa Nelson ◽

Julian A. Simon

Keyword(s):

De Novo ◽

Critical Role ◽

Salvage Pathway ◽

De Novo Synthesis ◽

Array Analysis ◽

Binding Partner ◽

Dependent Protein ◽

New Protein

ABSTRACT Nicotine adenine dinucleotide (NAD+) performs key roles in electron transport reactions, as a substrate for poly(ADP-ribose) polymerase and NAD+-dependent protein deacetylases. In the latter two processes, NAD+ is consumed and converted to ADP-ribose and nicotinamide. NAD+ levels can be maintained by regeneration of NAD+ from nicotinamide via a salvage pathway or by de novo synthesis of NAD+ from tryptophan. Both pathways are conserved from yeast to humans. We describe a critical role of the NAD+-dependent deacetylase Hst1p as a sensor of NAD+ levels and regulator of NAD+ biosynthesis. Using transcript arrays, we show that low NAD+ states specifically induce the de novo NAD+ biosynthesis genes while the genes in the salvage pathway remain unaffected. The NAD+-dependent deacetylase activity of Hst1p represses de novo NAD+ biosynthesis genes in the absence of new protein synthesis, suggesting a direct effect. The known Hst1p binding partner, Sum1p, is present at promoters of highly inducible NAD+ biosynthesis genes. The removal of HST1-mediated repression of the NAD+ de novo biosynthesis pathway leads to increased cellular NAD+ levels. Transcript array analysis shows that reduction in cellular NAD+ levels preferentially affects Hst1p-regulated genes in comparison to genes regulated with other NAD+-dependent deacetylases (Sir2p, Hst2p, Hst3p, and Hst4p). In vitro experiments demonstrate that Hst1p has relatively low affinity toward NAD+ in comparison to other NAD+-dependent enzymes. These findings suggest that Hst1p serves as a cellular NAD+ sensor that monitors and regulates cellular NAD+ levels.

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SCAP/SREBP pathway is required for the full steroidogenic response to cyclic AMP

Proceedings of the National Academy of Sciences ◽

10.1073/pnas.1611424113 ◽

2016 ◽

Vol 113 (38) ◽

pp. E5685-E5693 ◽

Cited By ~ 18

Author(s):

Masami Shimizu-Albergine ◽

Brian Van Yserloo ◽

Martin G. Golkowski ◽

Shao-En Ong ◽

Joseph A. Beavo ◽

...

Keyword(s):

Cyclic Amp ◽

Leydig Cells ◽

De Novo ◽

Regulatory Element ◽

De Novo Synthesis ◽

Intracellular Lipid ◽

Element Binding Protein ◽

Short Palindromic Repeat ◽

Sterol Regulatory Element

Luteinizing hormone (LH) stimulates steroidogenesis largely through a surge in cyclic AMP (cAMP). Steroidogenic rates are also critically dependent on the availability of cholesterol at mitochondrial sites of synthesis. This cholesterol is provided by cellular uptake of lipoproteins, mobilization of intracellular lipid, and de novo synthesis. Whether and how these pathways are coordinated by cAMP are poorly understood. Recent phosphoproteomic analyses of cAMP-dependent phosphorylation sites in MA10 Leydig cells suggested that cAMP regulates multiple steps in these processes, including activation of the SCAP/SREBP pathway. SCAP [sterol-regulatory element-binding protein (SREBP) cleavage-activating protein] acts as a cholesterol sensor responsible for regulating intracellular cholesterol balance. Its role in cAMP-mediated control of steroidogenesis has not been explored. We used two CRISPR (clustered regularly interspaced short palindromic repeat)-Cas9 (CRISPR associated protein 9) knockout approaches to test the role of SCAP in steroidogenesis. Our results demonstrate that SCAP is required for progesterone production induced by concurrent inhibition of the cAMP phosphodiesterases PDE4 and PDE8. These inhibitors increased SCAP phosphorylation, SREBP2 activation, and subsequent expression of cholesterol biosynthetic genes, whereas SCAP deficiency largely prevented these effects. Reexpression of SCAP in SCAP-deficient cells restored SREBP2 protein expression and partially restored steroidogenic responses, confirming the requirement of SCAP–SREBP2 in steroidogenesis. Inhibitors of 3-hydroxy-3-methylglutaryl-Coenzyme A reductase and isoprenylation attenuated, whereas exogenously provided cholesterol augmented, PDE inhibitor-induced steroidogenesis, suggesting that the cholesterol substrate needed for steroidogenesis is provided by both de novo synthesis and isoprenylation-dependent mechanisms. Overall, these results demonstrate a novel role for LH/cAMP in SCAP/SREBP activation and subsequent regulation of steroidogenesis.

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Vitamin E activates CRABP-II gene expression in cultured human fibroblasts, role of protein kinase C

FEBS Letters ◽

10.1016/j.febslet.2004.05.073 ◽

2004 ◽

Vol 569 (1-3) ◽

pp. 240-244 ◽

Cited By ~ 12

Author(s):

Amparo Gimeno ◽

Rosa Zaragozá ◽

Juan R Viña ◽

Vicente J Miralles

Keyword(s):

Gene Expression ◽

Protein Kinase C ◽

Vitamin E ◽

Protein Kinase ◽

Human Fibroblasts ◽

Kinase C ◽

Cultured Human Fibroblasts ◽

Crabp Ii

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Characterization of the AMP-binding protein gene family in Arabidopsis thaliana: will the real acyl-CoA synthetases please stand up?

Biochemical Society Transactions ◽

10.1042/bst0280955 ◽

2000 ◽

Vol 28 (6) ◽

pp. 955-957 ◽

Cited By ~ 8

Author(s):

J. Shockey ◽

J. Schnurr ◽

J. Browse

Keyword(s):

Protein Gene ◽

De Novo ◽

Functional Characterization ◽

De Novo Synthesis ◽

Triacylglycerol Composition ◽

Sequence Comparisons ◽

Triacylglycerol Metabolism ◽

Binding Protein Gene

One of the most prominent and important topics in modern agricultural biotechnology is the manipulation of oilseed triacylglycerol composition. Towards this goal, we have sought to identify and characterize acyl-CoA synthetases (ACSs), which play an important role in both de novo synthesis and modification of existing lipids. We have identified and cloned 20 different genes that bear strong sequence homology to known ACSs from other organisms. Through sequence comparisons and functional characterization, we have identified several members of this group that encode ACSs, while the other genes fall into the broader category of genes for AMP-binding proteins (AMPBPs). Distinguishing ACSs from AMPBPs will simplify our efforts to understand the role of ACS in triacylglycerol metabolism.

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