The NAD Biosynthesis Pathway Mediated by Nicotinamide Phosphoribosyltransferase Regulates Sir2 Activity in Mammalian Cells

Nicotinamide adenine dinucleotide (NAD) is an essential redox cofactor, but it also acts as a substrate for NAD-consuming enzymes, regulating cellular events such as DNA repair and gene expression. Since such processes are fundamental to support cancer cell survival and proliferation, sustained NAD production is a hallmark of many types of neoplasms. Depleting intratumor NAD levels, mainly through interference with the NAD-biosynthetic machinery, has emerged as a promising anti-cancer strategy. NAD can be generated from tryptophan or nicotinic acid. In addition, the “salvage pathway” of NAD production, which uses nicotinamide, a byproduct of NAD degradation, as a substrate, is also widely active in mammalian cells and appears to be highly exploited by a subset of human cancers. In fact, research has mainly focused on inhibiting the key enzyme of the latter NAD production route, nicotinamide phosphoribosyltransferase (NAMPT), leading to the identification of numerous inhibitors, including FK866 and CHS-828. Unfortunately, the clinical activity of these agents proved limited, suggesting that the approaches for targeting NAD production in tumors need to be refined. In this contribution, we highlight the recent advancements in this field, including an overview of the NAD-lowering compounds that have been reported so far and the related in vitro and in vivo studies. We also describe the key NAD-producing pathways and their regulation in cancer cells. Finally, we summarize the approaches that have been explored to optimize the therapeutic response to NAMPT inhibitors in cancer.

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BIOSINTESA FOLAT OLEH BAKTERI ASAM LAKTAT

AGROTECH : JURNAL ILMIAH TEKNOLOGI PERTANIAN ◽

10.37631/agrotech.v1i1.3 ◽

2019 ◽

Vol 1 (1) ◽

pp. 11-18

Author(s):

Siti Nur Purwandhani

Keyword(s):

Mammalian Cells ◽

Shikimate Pathway ◽

Aromatic Amino Acids ◽

Pentose Phosphate ◽

Biosynthesis Pathway ◽

Aminobenzoic Acid ◽

Dna And Rna ◽

Folate Biosynthesis ◽

Rna Biosynthesis ◽

Micro Organisms

Folate, an important B-group vitamin, participates in many metabolic pathways such as DNA and RNA biosynthesis and amino acid inter-conversions. Mammalian cells cannot synthesize folate; therefore, an exogenous supply of this vitamin is necessary to prevent nutritional deficiency. Folic acid is a composite molecule, being made up of three parts: a pteridine ring system (6-methylpterin), para-aminobenzoic acid , and glutamic acid . The folate biosynthesis pathway in micro-organisms can be divided in several parts. The pteridine proportion of folate is made from GTP, that is synthesized in the purine biosynthesis pathway. p-Aminobenzoic acid originates from chorismate and can be synthesized via the same biosynthesis pathways required for the aromatic amino acids, involving glycolysis, pentose phosphate pathway and shikimate pathway. The third component of a folate molecule is glutamate, that is normally taken up from the medium. This review will focus on biosynthesis and folate production by lactic acid bacteria and the folate level production in fermented product.

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Organ protection by caloric restriction depends on activation of the de novo NAD+ synthesis pathway

10.1101/2021.08.20.457042 ◽

2021 ◽

Author(s):

Martin Richard Spaeth ◽

K. Johanna R. Hoyer-Allo ◽

Marc Johnsen ◽

Martin Hoehne ◽

Christina Lucas ◽

...

Keyword(s):

Caloric Restriction ◽

Molecular Mechanisms ◽

De Novo ◽

Kidney Injury ◽

Valuable Insight ◽

Biosynthesis Pathway ◽

Organ Protection ◽

Nad Biosynthesis ◽

Nad Synthesis ◽

The Impact

Therapeutic strategies to treat acute kidney injury (AKI) are lacking in clinical practice. Interestingly, preconditioning by hypoxia (HP) and caloric restriction (CR) is highly protective in rodent AKI models. However, the underlying molecular mechanisms of this process are unknown. A comparative transcriptome analysis of murine kidneys after HP and CR identified Kynureninase (KYNU) as a common downstream target. Using a newly generated KYNU-deficient mouse line, we show that KYNU strongly contributes to the protective effect of preconditioning. Metabolome, transcriptome and proteome analyses reveal the KYNU-dependent de novo nicotinamide adenine dinucleotide (NAD+) biosynthesis pathway as necessary for CR-associated maintenance of NAD+ levels. Importantly, the impact of CR on the de novo NAD+ biosynthesis pathway can be recapitulated in humans. These findings provide a valuable insight into the molecular mechanisms mediating protection upon preconditioning and point towards the de novo branch of NAD+ biosynthesis as a conserved target in nephroprotection.

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Alternative NAD+ biosynthesis pathway activated by energy stress stimulates glycolysis in cardiac cells

Archives of Cardiovascular Diseases Supplements ◽

10.1016/j.acvdsp.2018.02.115 ◽

2018 ◽

Vol 10 (2) ◽

pp. 229

Author(s):

R. Deloux ◽

C. Tannous ◽

N. Diguet ◽

Z. Li ◽

M. Mericskay

Keyword(s):

Cardiac Cells ◽

Biosynthesis Pathway ◽

Nad Biosynthesis ◽

Energy Stress

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Genetic profiling of the isoprenoid and sterol biosynthesis pathways of Trypanosoma cruzi

10.7287/peerj.preprints.44 ◽

2013 ◽

Author(s):

Raul O Cosentino ◽

Patricio Diosque ◽

Fernán Agüero

Keyword(s):

Comparative Analysis ◽

Trypanosoma Cruzi ◽

Mammalian Cells ◽

Purifying Selection ◽

Structural Data ◽

Sterol Biosynthesis ◽

Biosynthesis Pathway ◽

Oxidase Gene ◽

Essential Information ◽

Genetic Profiling

Background. Sterols such as cholesterol, are important components of cellular membranes. But unlike mammalian cells, the main sterols found in the membranes of trypanosomes and fungi are ergosterol, and other 24-methyl sterols, which are required for growth and viability. In spite of this strict requirement, this group of organisms have evolved different strategies to produce and/or obtain sterols. Trypanosoma cruzi is the causative agent of Chagas Disease. In this parasite, one of the few validated targets for chemotherapeutic intervention is the sterol biosynthesis pathway. In this work we present a study of the genetic diversity observed in genes of the isoprenoid and sterol biosynthesis pathways in T. cruzi, and a comparative analysis of the diversity found in other trypanosomatids. Methodology/Principal Findings. Using a number of bioinformatic strategies, we first completed a number of holes in the pathway by identifying the sequences of genes that were missing and/or were truncated in the draft T. cruzi genome. Based on this analysis we identified a non-orthologous homolog of the yeast ERG25 gene (sterol methyl oxidase, SMO) and propose that the orthologs of ERG25 have been lost in trypanosomes (but not in leishmanias). Next, starting from a set of 16 T. cruzi strains representative of six major evolutionary lineages, we have amplified and sequenced ~ 24Kbp from 18 genes of the pathway, and identified a total of 975 SNPs or fixed differences, of which 28% represent nonsynonymous changes. We observed different patterns of accumulation of nucleotide changes for different genes of the pathway, from genes with a density of substitutions ranging from those close to the average (~2.5/100 bp) to some showing a high number of changes (11.4/100 bp, for a putative lathosterol oxidase gene). The majority of genes are under apparent purifying selection. However, two genes (TcPMK, TcSMO-like) have a ratio of nonsynonymous to synonymous changes that is close to neutrality. None of the nonsynonymous changes identified affect a catalytic or a ligand binding site residue. However, after mapping these changes on top of available structural data, we identified a number of changes that are in the close vicinity (7 Angstrom) of key residues, and that could therefore be functionally important. A comparative analysis of the corresponding T. brucei and Leishmania genes, obtained from available complete genomes highlights a high degree of conservation of the pathway, but with differences in the genes that are under apparent purifying selection in each case. Conclusions/Significance. We have identified a number of genes of the sterol biosynthesis pathway that were missing from the T. cruzi genome assembly. Also, we have identified unequal apparent selection acting on these genes, which may provide essential information for the future of drug development studies focused on this pathway.

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Genetic profiling of the isoprenoid and sterol biosynthesis pathways of Trypanosoma cruzi

10.7287/peerj.preprints.44v1 ◽

2013 ◽

Author(s):

Raul O Cosentino ◽

Patricio Diosque ◽

Fernán Agüero

Keyword(s):

Comparative Analysis ◽

Trypanosoma Cruzi ◽

Mammalian Cells ◽

Purifying Selection ◽

Structural Data ◽

Sterol Biosynthesis ◽

Biosynthesis Pathway ◽

Oxidase Gene ◽

Essential Information ◽

Genetic Profiling

Background. Sterols such as cholesterol, are important components of cellular membranes. But unlike mammalian cells, the main sterols found in the membranes of trypanosomes and fungi are ergosterol, and other 24-methyl sterols, which are required for growth and viability. In spite of this strict requirement, this group of organisms have evolved different strategies to produce and/or obtain sterols. Trypanosoma cruzi is the causative agent of Chagas Disease. In this parasite, one of the few validated targets for chemotherapeutic intervention is the sterol biosynthesis pathway. In this work we present a study of the genetic diversity observed in genes of the isoprenoid and sterol biosynthesis pathways in T. cruzi, and a comparative analysis of the diversity found in other trypanosomatids. Methodology/Principal Findings. Using a number of bioinformatic strategies, we first completed a number of holes in the pathway by identifying the sequences of genes that were missing and/or were truncated in the draft T. cruzi genome. Based on this analysis we identified a non-orthologous homolog of the yeast ERG25 gene (sterol methyl oxidase, SMO) and propose that the orthologs of ERG25 have been lost in trypanosomes (but not in leishmanias). Next, starting from a set of 16 T. cruzi strains representative of six major evolutionary lineages, we have amplified and sequenced ~ 24Kbp from 18 genes of the pathway, and identified a total of 975 SNPs or fixed differences, of which 28% represent nonsynonymous changes. We observed different patterns of accumulation of nucleotide changes for different genes of the pathway, from genes with a density of substitutions ranging from those close to the average (~2.5/100 bp) to some showing a high number of changes (11.4/100 bp, for a putative lathosterol oxidase gene). The majority of genes are under apparent purifying selection. However, two genes (TcPMK, TcSMO-like) have a ratio of nonsynonymous to synonymous changes that is close to neutrality. None of the nonsynonymous changes identified affect a catalytic or a ligand binding site residue. However, after mapping these changes on top of available structural data, we identified a number of changes that are in the close vicinity (7 Angstrom) of key residues, and that could therefore be functionally important. A comparative analysis of the corresponding T. brucei and Leishmania genes, obtained from available complete genomes highlights a high degree of conservation of the pathway, but with differences in the genes that are under apparent purifying selection in each case. Conclusions/Significance. We have identified a number of genes of the sterol biosynthesis pathway that were missing from the T. cruzi genome assembly. Also, we have identified unequal apparent selection acting on these genes, which may provide essential information for the future of drug development studies focused on this pathway.

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