Cell type-specific regulation of the pentose phoshate pathway during development and metabolic stress-driven autoimmune diseases: Relevance for inflammatory liver, renal, endocrine, cardiovascular and neurobehavioral comorbidites, carcinogenesis, and aging

Autoimmunity Reviews, Journal Year: 2025, Volume and Issue: 24(5), P. 103781 - 103781

Published: Feb. 24, 2025

Language: Английский

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Regulation of and challenges in targeting NAD+ metabolism

Nature Reviews Molecular Cell Biology, Journal Year: 2024, Volume and Issue: 25(10), P. 822 - 840

Published: July 18, 2024

Language: Английский

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CD38 mediates nicotinamide mononucleotide base exchange to yield nicotinic acid mononucleotide

Journal of Biological Chemistry, Journal Year: 2025, Volume and Issue: unknown, P. 108248 - 108248

Published: Jan. 1, 2025

Language: Английский

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Impaired yolk sac NAD metabolism disrupts murine embryogenesis with relevance to human birth defects

Published: Jan. 31, 2025

Congenital malformations can originate from numerous genetic or non-genetic factors but in most cases the causes are unknown. Genetic disruption of nicotinamide adenine dinucleotide (NAD) de novo synthesis multiple malformations, collectively termed NAD Deficiency Disorder (CNDD), highlighting necessity this pathway during embryogenesis. Previous work mice shows that deficiency perturbs embryonic development specifically when organs forming. While is predominantly active liver postnatally, site activity prior to and organogenesis unknown.Here, we used a mouse model human CNDD assessed functionality livers extraembryonic tissues via gene expression, enzyme metabolic analyses. We found extra-embryonic visceral yolk sac endoderm exclusively synthesises early before takes over function. Under CNDD-inducing conditions, sacs had reduced levels altered NAD-related profiles, affecting embryo metabolism. Expression requisite genes conserved equivalent cell type humans.Our findings show sac-mediated essential for embryogenesis its perturbation CNDD. As functionally homologous, our data improve understanding congenital malformation causation.

Language: Английский

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Impaired yolk sac NAD metabolism disrupts murine embryogenesis with relevance to human birth defects

eLife, Journal Year: 2025, Volume and Issue: 13

Published: March 6, 2025

Congenital malformations can originate from numerous genetic or non-genetic factors but in most cases the causes are unknown. Genetic disruption of nicotinamide adenine dinucleotide (NAD) de novo synthesis multiple malformations, collectively termed NAD Deficiency Disorder (CNDD), highlighting necessity this pathway during embryogenesis. Previous work mice shows that deficiency perturbs embryonic development specifically when organs forming. While is predominantly active liver postnatally, site activity prior to and organogenesis Here, we used a mouse model human CNDD assessed functionality livers extraembryonic tissues via gene expression, enzyme metabolic analyses. We found extra-embryonic visceral yolk sac endoderm exclusively synthesises early before takes over function. Under CNDD-inducing conditions, sacs had reduced levels altered NAD-related profiles, affecting embryo metabolism. Expression requisite genes conserved equivalent cell type humans. Our findings show sac-mediated essential for embryogenesis its perturbation CNDD. As functionally homologous, our data improve understanding congenital malformation causation.

Language: Английский

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Advances in human glutamine-hydrolyzing synthetases and their therapeutic potential

Frontiers in Chemical Biology, Journal Year: 2024, Volume and Issue: 3

Published: June 6, 2024

Bifunctional enzymes, characterized by their dual active sites, enable efficient chemical conversion and substrate channeling using elegant coupling mechanisms to coordinate the two sites. In humans, several bifunctional enzymes synthesize de novo carbon-nitrogen bonds hydrolyzing glutamine ATP in distinct Notable examples include guanosine monophosphate synthetase, cytidine triphosphate phosphoribosylformyl-glycinamidine synthase, asparagine nicotinamide adenine dinucleotide synthetase. A more complex example of multifunctional glutamine-hydrolyzing synthetases humans is carbamoyl phosphate These are crucial for biosynthesis amino acids, nucleic co-factors, thereby playing pivotal roles human health. This review delineates recent progress understanding structural characteristics, regulatory mechanisms, disease relevance humans. Insights into catalysis activity regulation offer potential pathways developing novel therapeutics.

Language: Английский

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Impaired yolk sac NAD metabolism disrupts murine embryogenesis with relevance to human birth defects

Published: Aug. 22, 2024

Severe congenital malformations are a frequent cause of premature death and morbidity in children worldwide. Malformations can originate from numerous genetic or non-genetic factors but most cases the underlying causes unknown. Genetic disruption nicotinamide adenine dinucleotide (NAD) de novo synthesis drives formation multiple malformations, collectively termed Congenital NAD Deficiency Disorder (CNDD), highlighting necessity this pathway during embryogenesis. Previous work mice shows that deficiency perturbs embryonic development specifically critical period when organs forming. While is predominantly active liver postnatally, site activity prior to organogenesis Here, we used mouse model human CNDD applied gene expression, enzyme metabolic analyses assess functionality extraembryonic tissues. We found extra-embryonic visceral yolk sac endoderm exclusively performs early before takes over function. Furthermore, under CNDD-inducing conditions, sacs had reduced levels altered NAD-related profiles which affected embryo metabolism. Expression requisite genes for conserved equivalent cell type humans. Our findings show sac-mediated essential perturbation results CNDD. Given functional homology between sacs, our data improve understanding malformation causation.

Language: Английский

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Impaired yolk sac NAD metabolism disrupts murine embryogenesis with relevance to human birth defects

bioRxiv (Cold Spring Harbor Laboratory), Journal Year: 2024, Volume and Issue: unknown

Published: May 8, 2024

Abstract Congenital malformations can originate from numerous genetic or non-genetic factors but in most cases the causes are unknown. Genetic disruption of nicotinamide adenine dinucleotide (NAD) de novo synthesis multiple malformations, collectively termed NAD Deficiency Disorder (CNDD), highlighting necessity this pathway during embryogenesis. Previous work mice shows that deficiency perturbs embryonic development specifically when organs forming. While is predominantly active liver postnatally, site activity prior to and organogenesis Here, we used a mouse model human CNDD assessed functionality livers extraembryonic tissues via gene expression, enzyme metabolic analyses. We found extra-embryonic visceral yolk sac endoderm exclusively synthesises early before takes over function. Under CNDD-inducing conditions, sacs had reduced levels altered NAD-related profiles, affecting embryo metabolism. Expression requisite genes conserved equivalent cell type humans. Our findings show sac-mediated essential for embryogenesis its perturbation CNDD. As functionally homologous, our data improve understanding congenital malformation causation.

Language: Английский

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CD38 mediates nicotinamide mononucleotide (NMN) base exchange to yield nicotinic acid mononucleotide (NaMN)

bioRxiv (Cold Spring Harbor Laboratory), Journal Year: 2024, Volume and Issue: unknown

Published: Aug. 8, 2024

Abstract Nicotinamide mononucleotide (NMN) is a widely investigated metabolic precursor to the prominent redox cofactor nicotinamide adenine dinucleotide (NAD + ), where it assumed that delivery of this compound results in its direct incorporation into NAD via canonical salvage / recycling pathway. Surprisingly, treatment with pathway intermediate leads increases nicotinic acid (NaMN) and (NaAD), two members Preiss-Handler de novo pathways. In mammals, these pathways are not known intersect prior production . Here, we show cell surface enzyme CD38 can mediate base exchange reaction on NMN, whereby ring exchanged free yield NaMN, vivo small molecule inhibition abolishing NMN-induced increase NaMN NaAD. Together, data demonstrate new mechanism by which intermediates mammalian biosynthesis.

Language: Английский

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Impaired yolk sac NAD metabolism disrupts murine embryogenesis with relevance to human birth defects

Published: Aug. 22, 2024

Congenital malformations can originate from numerous genetic or non-genetic factors but in most cases the causes are unknown. Genetic disruption of nicotinamide adenine dinucleotide (NAD) de novo synthesis multiple malformations, collectively termed NAD Deficiency Disorder (CNDD), highlighting necessity this pathway during embryogenesis. Previous work mice shows that deficiency perturbs embryonic development specifically when organs forming. While is predominantly active liver postnatally, site activity prior to and organogenesis Here, we used a mouse model human CNDD assessed functionality livers extraembryonic tissues via gene expression, enzyme metabolic analyses. We found extra-embryonic visceral yolk sac endoderm exclusively synthesises early before takes over function. Under CNDD-inducing conditions, sacs had reduced levels altered NAD-related profiles, affecting embryo metabolism. Expression requisite genes conserved equivalent cell type humans. Our findings show sac-mediated essential for embryogenesis its perturbation CNDD. As functionally homologous, our data improve understanding congenital malformation causation.

Language: Английский

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