Last update 01 Nov 2024

NADSYN1

Last update 01 Nov 2024

Basic Info

Synonyms

FLJ10631, Glutamine-dependent NAD(+) synthetase, NAD synthetase 1

+ [3]

Introduction

Catalyzes the final step of the nicotinamide adenine dinucleotide (NAD) de novo synthesis pathway, the ATP-dependent amidation of deamido-NAD using L-glutamine as a nitrogen source.

Drugs associated with NADSYN1

Nicotinamide mononucleotide

Target

NADSYN1

Mechanism

NADSYN1 modulators

Active Org.

Metro International Biotech LLC [+4]

Originator Org.

Metro International Biotech LLC

Active Indication

Diabetes Mellitus, Type 2 [+5]

Inactive Indication

Friedreich Ataxia

Drug Highest PhasePhase 2

First Approval Ctry. / Loc.-

First Approval Date20 Jan 1800

CNX-016

Target

NADSYN1

Mechanism

NADSYN1 modulators

Active Org.-

Originator Org.

Connexios Life Sciences Pvt Ltd.

Active Indication-

Inactive Indication

Diabetes Mellitus, Type 2

Drug Highest PhasePending

First Approval Ctry. / Loc.-

First Approval Date20 Jan 1800

Clinical Trials associated with NADSYN1

NCT05878119 / RecruitingPhase 2

Effects of MIB-626 (β-Nicotinamide Mononucleotide) With and Without A High-Intensity Multi-Dimensional Exercise Training Program on Physical Performance, Muscle Bioenergetics, and Neuropsychological Performance in Highly Fit Young Adults

A single-center, randomized, placebo-controlled study in community dwelling, healthy, regularly exercising, highly physically fit men and women, 19 to 40 years. Eligible participants will be randomized to receive either 1000 mg NMN or placebo twice daily for 10 weeks.

Start Date25 Oct 2023

Sponsor / Collaborator

Metro International Biotech LLC

NCT06036355 / Not yet recruitingEarly Phase 1

THE Exploratory Study on the Biological Function of Dendritic Cells In Vivo Supported by Nicotinamide Mononucleotide (Vital NAD)

The main purpose of this study is to explore the PK/PD changes of NMN and DC cells after oral NMN combined with DC cells injection in patients after tumor surgery, and evaluate the biological age of adults, TCR diversity, SiRT1 expression level, SF-36 quality of life, OS, antigen specific immune response (TAA), cytokines and so on. In this study, 20 postoperative tumor patients who meet the entry and excretion criteria were recruited to explore the clinical potential of NMN combined with DC cell vaccine.

Start Date30 Sep 2023

Sponsor / Collaborator

Shanghai Cell Therapy Group Co., Ltd.

NCT05984550 / Not yet recruitingEarly Phase 1

The Exploratory Study on the Nicotinamide Mononucleotide (Vital NAD ) to Promote the Rejuvenation of the Peripheral Blood Immune Cells of Adults.

The purpose of this study is to investigate the changes in adult peripheral blood immune cell subpopulations, subpopulations, and cell functional status before and after intervention with Nicotinamide Mononucleotide (Vital NAD ) as NAD+ supplement for a certain period of time。To Explore and validate the biological functions of Nicotinamide Mononucleotide (Vital NAD ) of rejuvenation of the Peripheral blood immune cells of Adults.

Start Date01 Aug 2023

Sponsor / Collaborator

Shanghai Cell Therapy Group Co., Ltd.

100 Clinical Results associated with NADSYN1

100 Translational Medicine associated with NADSYN1

0 Patents (Medical) associated with NADSYN1

211

Literatures (Medical) associated with NADSYN1

01 Jun 2024·International Immunopharmacology

Inhibiting the SARM1-NAD+ axis reduces oxidative stress-induced damage to retinal and nerve cells

Article

Author: Zhou, Biting ; Zhang, Yannan ; Yang, Juhua ; Yao, Yihua ; Zhu, Yihua

Retinal neurodegenerative diseases are a category of refractory blinding eye conditions closely associated with oxidative stress induced by mitochondrial dysfunction in retinal cells. SARM1, a core driver molecule leading to axonal degeneration, possesses NAD⁺ enzyme (NADase) activity. However, the role of the SARM1-NAD⁺ axis in oxidative stress-induced retinal cell death remains unclear. Here, we employed the SARM1 NADase inhibitor DSRM-3716 and established a glucose oxidase (GOx)-induced oxidative stress cell model. We found that compared to the GOx group, the DSRM-3716 pre-treated group reduced the hydrolysis of NAD⁺, inhibited the elevation of oxidative stress markers induced by GOx, decreased mitochondrial dysfunction, lowered the phosphorylation level of JNK, and attenuated the occurrence of pyroptosis in retinal and nerve cells, thereby providing protection for neurite growth. Further utilization of the JNK activator Anisomycin activated JNK, revealed that the JNK/c-Jun pathway down-regulated NMNAT2 expression. Consequently, it reduced cellular NAD⁺ synthesis, exacerbated mitochondrial dysfunction and cell pyroptosis, and reversed the protective effect of DSRM-3716 on cells. In summary, the inhibition of SARM1 NADase activity substantially mitigates oxidative damage to retinal cells and mitochondrial damage. Additionally, JNK simultaneously serves as both an upstream and downstream regulator in the SARM1-NAD⁺ axis, regulating retinal cell pyroptosis and neurite injury. Thus, this study provides new insights into the pathological processes of retinal cell oxidative stress and identifies potential therapeutic targets for retinal neurodegenerative diseases.

01 May 2024·Gene

Single-nucleotide polymorphisms related to vitamin D metabolism and severity or mortality of COVID-19: A systematic review and meta-analysis

Review

Author: Crispim Lopo de Abreu, Micaela ; Moriel, Patricia ; Tiemi Siguemoto, Júlia ; Berlofa Visacri, Marília ; Moriel Pincinato, Pedro ; Dagli-Hernandez, Carolina ; Rotta, Inajara ; de Souza Nicoletti, Aline ; Regina da Silva Correa da Ronda, Carla ; Motta Neri, Carolini ; de Carvalho Pincinato, Eder

This systematic review and meta-analysis aimed to verify the association between single-nucleotide polymorphisms (SNPs) in vitamin D-related genes and the severity or mortality of coronavirus disease 19 (COVID-19). We systematically searched PubMed, BVS/Bireme, Scopus, Embase, and Web of Science for relevant studies published until November 24, 2023. Twelve studies were included. Thirty-one SNPs related to four genes were studied (VDR, 13 SNPs; GC, 6 SNPs; DHCR7/NADSYN1, 6 SNPs; CYP2R1, 6 SNPs). Eight SNPs were examined in two or more studies (VDR rs731236, rs2228570, rs1544410, rs7975232, rs739837, rs757343, rs11568820, and rs4516035). Meta-analysis showed a significant association between the VDR rs1544410 Bb + bb genotype and b allele and an increased odds of developing severe/critical COVID-19 (Bb + bb vs. BB = 2 studies, OR = 1.73, 95% confidence interval (CI): 1.16-2.57, P = 0.007, I² = 0%; b allele vs. B allele = 2 studies, OR = 1.31, 95% CI: 1.03-1.67; P = 0.03; I² = 0%). Regarding the mortality rate, VDR rs731236 TT-genotype, TT + Tt genotype, and T allele; VDR rs1544410 bb-genotype, Bb + bb genotype, and b allele; VDR rs7975232 AA-genotype, AA + Aa genotype, and A allele; and VDR rs2228570 ff-genotype, Ff + ff genotype, and f allele were associated with increased odds of death due to COVID-19. In conclusion, the present study suggests that SNPs rs1544410 may serve as a predictive biomarker for COVID-19 severity and rs731236, rs1544410, rs7975232, and rs2228570 as predictive biomarkers for COVID-19 mortality. More well-designed studies involving a larger number of COVID-19 patients are required to validate and replicate these findings.

15 Feb 2024·Journal of Clinical Investigation

A metabolic signature for NADSYN1-dependent congenital NAD deficiency disorder

Article

Author: Portelli, Stephanie ; Lermine, Alban ; Wright, Helen ; Iyer, Kavitha ; Poulton, Cathryn ; Andrews, Israel D ; Heath, Oliver ; Pais, Lynn S ; Pitt, James ; Bozon, Kayleigh ; Tan, Tiong Y ; Brown, Natasha J ; Bouman, Katelijne ; Alankarage, Dimuthu ; McDermott, John H ; Martin, Ella Mma ; Nguyen, Vivien ; Sheng, Delicia Z ; Keren, Boris ; Prakash, Supraja ; Dunwoodie, Sally L ; Jeffries, Lauren ; Grebe, Theresa A ; Chong, Karen ; Wentzensen, Ingrid M ; Szot, Justin O ; Pruniski, Brianna ; Cuny, Hartmut ; Chapman, Gavin ; Corsten-Janssen, Nicole ; Ji, Weizhen ; Lakhani, Saquib A ; Gereis, Jessica M ; Vincent-Delormé, Catherine ; Chitayat, David ; Ascher, David B ; Wise, Cheryl A ; Burkitt-Wright, Emma ; Hunter, Matthew F

Nicotinamide adenine dinucleotide (NAD) is essential for embryonic development. To date, biallelic loss-of-function variants in 3 genes encoding nonredundant enzymes of the NAD de novo synthesis pathway - KYNU, HAAO, and NADSYN1 - have been identified in humans with congenital malformations defined as congenital NAD deficiency disorder (CNDD). Here, we identified 13 further individuals with biallelic NADSYN1 variants predicted to be damaging, and phenotypes ranging from multiple severe malformations to the complete absence of malformation. Enzymatic assessment of variant deleteriousness in vitro revealed protein domain-specific perturbation, complemented by protein structure modeling in silico. We reproduced NADSYN1-dependent CNDD in mice and assessed various maternal NAD precursor supplementation strategies to prevent adverse pregnancy outcomes. While for Nadsyn1+/- mothers, any B3 vitamer was suitable to raise NAD, preventing embryo loss and malformation, Nadsyn1-/- mothers required supplementation with amidated NAD precursors (nicotinamide or nicotinamide mononucleotide) bypassing their metabolic block. The circulatory NAD metabolome in mice and humans before and after NAD precursor supplementation revealed a consistent metabolic signature with utility for patient identification. Our data collectively improve clinical diagnostics of NADSYN1-dependent CNDD, provide guidance for the therapeutic prevention of CNDD, and suggest an ongoing need to maintain NAD levels via amidated NAD precursor supplementation after birth.

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