Nuclear Magnetic Resonance Spectroscopy Data Research Articles

1H-NMR-Based Metabolomic Study of Potato Cultivars, Markies and Fianna, Exposed to Different Water Regimes

This study investigated the effects of varying soil moisture conditions (through either flooding, drought, or provision of a moderate water supply) on the metabolomic profile of two potato cultivars, namely, Markies and Fianna. Representative tubers of the treated plants were collected 91 days after planting. The samples were freeze-dried, and ground to a fine powder in liquid nitrogen. The fine powder of the tuber samples was analyzed by nuclear magnetic resonance spectroscopy (NMR) to identify their metabolomic profiles. The NMR data was analyzed using principal component analysis and orthogonal partial least square-discriminant analysis to identify any variations between the treatments. In both models, plants exposed to drought clearly separated from the plants that received either excess or moderate water (control). The potato tubers that experienced drought and flood treatments had the highest quantities of aspartic acid, asparagine, and isoleucine. Furthermore, the potatoes exposed to either drought or flood had higher levels of valine and leucine (which are essential for plant defense and resistance against plant pathogens). Potato plants can respond metabolically to varying soil moisture stress.

A New Labdane-Type Diterpene, 6-O-Acetyl-(12R)-epiblumdane, from Stevia rebaudiana Leaves with Insulin Secretion Effect.

Stevia rebaudiana (Asteraceae), commonly known as candyleaf, sweetleaf, or sugarleaf, is a branched bushy shrub whose leaves are used as a natural sweetener owing to the high content of sweet diterpenes. As part of our ongoing work to identify structurally novel and bioactive natural products, phytochemical investigation of the ethanolic extract of S. rebaudiana leaves led to the isolation of one new labdane-type diterpene, 6-O-acetyl-(12R)-epiblumdane (1), and nine known terpenoids, including six diterpenes (2–6 and 10), two monoterpenes (7 and 8), and one triterpene (9). The structure of the new compound 1 was elucidated via analysis of one- and two-dimensional nuclear magnetic resonance (NMR) spectroscopic data and high-resolution electrospray ionization mass spectrometry data, and its absolute configuration was established using electronic circular dichroism (ECD) calculations and gauge-including atomic orbital NMR chemical shift calculations, followed by DP4 + probability analysis. The isolated compounds 1–10 were evaluated for their effects on glucose-stimulated insulin secretion in the INS-1 rat pancreatic β-cell line. The new compound 1, 6-O-acetyl-(12R)-epiblumdane, stimulated glucose-stimulated insulin secretion in INS-1 pancreatic β-cells without inducing cytotoxicity. Thus, 6-O-acetyl-(12R)-epiblumdane (1), an active compound derived from S. rebaudiana leaves, can be used as a potential therapeutic agent to prevent type 2 diabetes.

Green Synthesis and Anticancer Potential of 1,4-Dihydropyridines-Based Triazole Derivatives: In Silico and In Vitro Study.

A library of 1,4-dihydropyridine-based 1,2,3-triazol derivatives has been designed, synthesized, and evaluated their cytotoxic potential on colorectal adenocarcinoma (Caco-2) cell lines. All compounds were characterized and identified based on their 1H and 13C NMR (Nuclear Magnetic Resonance) spectroscopic data. Furthermore, molecular docking of best anticancer hits with target proteins (protein kinase CK2α, tankyrase1, and tankyrase2) has been performed. Our results implicated that most of these compounds have significant antiproliferative activity with IC50 values between 0.63 ± 0.05 and 5.68 ± 0.14 µM. Moreover, the mechanism of action of most active compounds 13ab′ and 13ad′ suggested that they induce cell death through apoptosis in the late apoptotic phase as well as dead phase, and they could promote cell cycle arrest at the G2/M phase. Furthermore, the molecular docking study illustrated that 13ad′ possesses better binding interaction with the catalytic residues of target proteins involved in cell proliferation and antiapoptotic pathways. Based on our in vitro and in silico study, 13ad′ was found to be a highly effective anti-cancerous compound. The present data indicate that dihydropyridine-linked 1,2,3-triazole conjugates can be generated as potent anticancer agents.

Structural Characterization of Withanolide Glycosides from the Roots of Withania somnifera and Their Potential Biological Activities.

Withania somnifera (Solanaceae), commonly known as “ashwagandha”, is an ayurvedic medicinal plant that has been used for promoting good health and longevity. As part of our ongoing natural product research for the discovery of bioactive phytochemicals with novel structures, we conducted a phytochemical analysis of W. somnifera root, commonly used as an herbal medicine part. The phytochemical investigation aided by liquid chromatography-mass spectrometry (LC/MS)-based analysis led to the isolation of four withanolide glycosides (1–4), including one new compound, withanoside XII (1), from the methanol (MeOH) extract of W. somnifera root. The structure of the new compound was determined by nuclear magnetic resonance (NMR) spectroscopic data, high-resolution (HR) electrospray ionization (ESI) mass spectroscopy (MS), and electronic circular dichroism (ECD) data as well as enzymatic hydrolysis followed by LC/MS analysis. In addition, enzymatic hydrolysis of 1 afforded an aglycone (1a) of 1, which was identified as a new compound, withanoside XIIa (1a), by the interpretation of NMR spectroscopic data, HR-ESIMS, and ECD data. To the best of our knowledge, the structure of compound 2 (withagenin A diglucoside) was previously proposed by HRMS and MS/MS spectral data, without NMR experiment, and the physical and spectroscopic data of withagenin A diglucoside (2) are reported in this study for the first time. All the isolated compounds were evaluated for their anti-Helicobacter pylori, anti-oxidant, and anti-inflammatory activities. In the anti-Helicobacter pylori activity assay, compound 2 showed weak anti-H. pylori activity with 7.8% inhibition. All the isolated compounds showed significant ABTS radical scavenging activity. However, all isolates failed to show inhibitory activity against nitric oxide (NO) production in lipopolysaccharide-stimulated RAW 264.7 macrophage cells. This study demonstrated the experimental support that the W. somnifera root is rich in withanolides, and it can be a valuable natural resource for bioactive withanolides.

Heterotrimetallic Double Cavity Cages: Syntheses and Selective Guest Binding

AbstractA strategy for the generation of heterotrimetallic double cavity (DC) cages [PdnPtmL4]6+ (DC1: n=1, m=2; and DC2: n=2, m=1) is reported. The DC cages were generated by combining an inert platinum(II) tetrapyridylaldehyde complex with a suitably substituted pyridylamine and PdII ions. 1H and DOSY nuclear magnetic resonance spectroscopy (NMR) and electrospray ionization mass spectrometry (ESIMS) data were consistent with the formation of the DC architectures. DC1 and DC2 were shown to interact with several different guest molecules. The structure of DC1, which features two identical cavities, binding two 2,6‐diaminoanthraquinone (DAQ) guest molecules was determined by single‐crystal X‐ray crystallography. In addition, DC1 was shown to bind two molecules of 5‐fluorouracil (5‐FU) in a statistical (non‐cooperative) manner. In contrast, DC2, which features two different cage cavities, was found to interact with two different guests, 5‐FU and cisplatin, selectively.

Heterotrimetallic Double Cavity Cages: Syntheses and Selective Guest Binding.

A strategy for the generation of heterotrimetallic double cavity (DC) cages [Pd n Pt m L4]6+ (DC1: n=1, m=2; and DC2: n=2, m=1) is reported. The DC cages were generated by combining an inert platinum(II) tetrapyridylaldehyde complex with a suitably substituted pyridylamine and PdII ions. 1H and DOSY nuclear magnetic resonance spectroscopy (NMR) and electrospray ionization mass spectrometry (ESIMS) data were consistent with the formation of the DC architectures. DC1 and DC2 were shown to interact with several different guest molecules. The structure of DC1, which features two identical cavities, binding two 2,6‐diaminoanthraquinone (DAQ) guest molecules was determined by single‐crystal X‐ray crystallography. In addition, DC1 was shown to bind two molecules of 5‐fluorouracil (5‐FU) in a statistical (non‐cooperative) manner. In contrast, DC2, which features two different cage cavities, was found to interact with two different guests, 5‐FU and cisplatin, selectively.

Untargeted 1H-NMR Urine Metabolomic Analysis of Preterm Infants with Neonatal Sepsis

One of the most critical medical conditions occurring after preterm birth is neonatal sepsis, a systemic infection with high rates of morbidity and mortality, chiefly amongst neonates hospitalized in Neonatal Intensive Care Units (NICU). Neonatal sepsis is categorized as early-onset sepsis (EOS) and late-onset sepsis (LOS) regarding the time of the disease onset. The accurate early diagnosis or prognosis have hurdles to overcome, since there are not specific clinical signs or laboratory tests. Herein, a need for biomarkers presents, with the goals of aiding accurate medical treatment, reducing the clinical severity of symptoms and the hospitalization time. Through nuclear magnetic resonance (NMR) based metabolomics, we aim to investigate the urine metabolomic profile of septic neonates and reveal those metabolites which could be indicative for an initial discrimination between the diseased and the healthy ones. Multivariate and univariate statistical analysis between NMR spectroscopic data of urine samples from neonates that developed EOS, LOS, and a healthy control group revealed a discriminate metabolic profile of septic newborns. Gluconate, myo-inositol, betaine, taurine, lactose, glucose, creatinine and hippurate were the metabolites highlighted as significant in most comparisons.

Absolute configuration of cytotoxic anthraquinones from a Brazilian cave soil-derived fungus, Aspergillus sp. SDC28.

Microbial strains isolated from extreme and understudied environments, such as caves, are still poorly investigated for the production of bioactive secondary metabolites. Investigation of the ethyl acetate extract from the growth medium produced by the soil-derived fungus Aspergillus sp. SDC28, isolated from a Brazilian cave, yielded two anthraquinones: versicolorin C (1) and versiconol (2). The complete assignment of nuclear magnetic resonance and mass spectroscopic data of 1 and 2 was performed for the first time. Moreover, the yet unreported absolute configuration of both compounds was unambiguously established by analysis of experimental and theoretical electronic circular dichroism data. Vibrational circular dichroism was also applied to confirm the absolute stereochemistry of 2. Compounds 1 and 2 showed cytotoxic activity against human ovarian cancer cells (OVCAR3).

New Trichothecenes Isolated from the Marine Algicolous Fungus Trichoderma brevicompactum.

Eight trichothecenes, including four new compounds 1–4 and four known entities 5–8, together with one known cyclonerane (9) were isolated from the solid-state fermentation of Trichoderma brevicompactum NTU439 isolated from the marine alga Mastophora rosea. The structures of 1–9 were determined by 1D/2D NMR (nuclear magnetic resonance), MS (mass spectrometry), and IR (infrared spectroscopy) spectroscopic data. All of the compounds were evaluated for cytotoxic activity against HCT-116, PC-3, and SK-Hep-1 cancer cells by the SRB assay, and compound 8 showed promising cytotoxic activity against all three cancer cell lines with the IC50 values of 3.3 ± 0.3, 5.3 ± 0.3, and 1.8 ± 0.8 μM, respectively. Compounds 1–2, 4–6, and 7–8 potently inhibited LPS-induced NO production, and compounds 5 and 8 showed markedly inhibited gelatinolysis of MMP-9 in S1 protein-stimulated THP-1 monocytes.

Cytotoxic and other bioactivities of a novel and known sesquiterpene lactones isolated from Vernonia leopoldi (Sch. Bip. ex Walp.) Vatke in breast cancer cell lines

Vernonia leopoldi (Sch. Bip. ex Walp.) Vatke (Asteraceae) is one of the widely used anti-cancer traditional medicinal plants in Ethiopia, despite the lack of data to support its therapeutic efficacy. Here we describe the isolation of compounds from the plant and the investigation of their cytotoxicity and other bioactivities. We identified the novel sesquiterpene lactone (SL) 11ß,13-dihydrovernodalol along with the three other SLs (vernomenin, vernolepin, and 11ß,13-dihydrovernodalin) and three flavonoids (apigenin, eriodyctiol, and luteolin) isolated from this plant for the first time. The structures of all the compounds were established based on extensive analysis of nuclear magnetic resonance spectroscopic data and confirmed by high-resolution electrospray ionization mass spectrometry. We then studied the biological activities of the SLs and found that all were cytotoxic at low μM ranges against MCF-7 and JIMT-1 breast cancer cells as well as against the normal-like MCF-10A breast epithelial cells evaluated in a spectrophotometric assay. All the SLs significantly reduced JIMT-1 cell migration after 72 h of treatment with 2 μM concentrations in a wound healing assay. Treatment with all SLs reduced the aldehyde dehydrogenase expressing cancer stem cell sub-population of the JIMT-1 cells significantly, evaluated by flow cytometry. Only 11ß,13-dihydrovernodalin resulted in a significant inhibition of tumor necrosis factor-α-induced translocation of nuclear factor κB to the cell nucleus. In addition, we show that the reporter fluorophore nitrobenzoxadiazole (NBD) can successfully be conjugated with an SL and that this SL-NBD conjugate is taken up efficiently in JIMT-1 cells. Therefore, the overall bioactivities of the SL compounds and specifically their effects against the stemness of breast cancer cells make them prime candidates for further in-depth investigation.

Metabolomic Profiling of Different Maca Color Types Using Nuclear Magnetic Resonance Spectroscopy and Multivariate Data Analysis

This study aimed to explore significant differences in chemical composition among maca (Lepidium meyenii Walp.) types with different colors in Yunnan province, China. 1H-NMR spectroscopy, in combination with principal component analysis and partial least squares discriminant analysis, was used to investigate the compounds responsible for compositional differences. Different maca color types in Yunnan were clearly distinguished by 11 differential metabolites. Furthermore, network pharmacology results showed that 30 active components were related to Alzheimer’s disease. Nine intersecting compounds among the 11 differential metabolites and 30 active components, namely, lysine, isoleucine, phenylalanine, β-hydroxybutyrate, tryptophan, pyroglutamate, proline, glutamine, and fructose, were used as bioactive markers to identify different maca color types. The results showed the bioactive markers among different maca color types holistically, providing a scientific basis for assessing the quality of commercial products derived from different maca color types.

ANTIBACTERIAL COMPOUND FROM MARINE SPONGE DERIVED FUNGUS Aspergillus sydowii DC08

A bioactive compound was isolated from ethyl acetate extract of the marine sponge-derived fungus Aspergillus sydowii DC08. The compound's structural details were determined based on the study of nuclear magnetic resonance spectroscopy and mass spectrometric data. p-Iodonitrotetrazolium chloride (INT), a marker of bacterial growth, was used in the microdilution assay to assess the isolated compound's antibacterial efficacy. The isolated chemical was identified as sterigmatocystin (1) using spectroscopic data. This compound showed moderate activity against some pathogenic bacteria. The Minimum Inhibitory Concentration (MIC) values for this substance were 64, 128, 16, 32, and 32 µg/mL for Methicillin-Resistant Staphylococcus aureus (MRSA), Multi-Drug Resistant Pseudomonas aeruginosa (MDRPA), Escherichia coli, Staphylococcus aureus, and Pseudomonas aeruginosa, respectively.

Neuroprotective effects of a new triterpenoid from edible mushroom on oxidative stress and apoptosis through the BDNF/TrkB/ERK/CREB and Nrf2 signaling pathway in vitro and in vivo.

Inonotus obliquus (Fr.) Pilat is an edible mushroom which is used to produce tea and syrup due to its medicinal properties. In this study, 10 secondary metabolites (1-10), including a new lanostane triterpenoid named 2α-hydroxy-inotodiol (2α-HI, 1), were identified from the edible mushroom I. obliquus through high-resolution electrospray ionization mass spectrometry (HRESIMS) and nuclear magnetic resonance spectroscopy (NMR) data analysis. The neuroprotective function of all steroidal metabolites in H2O2-induced SH-SY5Y cells was investigated. The results showed that 2α-HI exhibited the most remarkable neuroprotective activity. In the meantime, 2α-HI significantly ameliorated oxidative stress damage, reactive oxygen species (ROS) accumulation and mitochondrial damage induced by H2O2 in SH-SY5Y cells. The Nrf2 siRNA and inhibitors transfected the SH-SY5Y cells, indicating the Nrf2 and BDNF/TrkB/ERK/CREB pathway mediated the neuroprotective effects of 2α-HI against the H2O2-stimulated oxidative stress and apoptosis. Moreover, the neuroprotection of 2α-HI was preliminarily verified in zebrafish. In conclusion, this research was the first to confirm that 2α-HI could effectively protect SH-SY5Y cells against H2O2-induced oxidative stress and apoptosis via the Nrf2 and BDNF/TrkB/ERK/CREB signaling pathway. Hence, this mushroom could be a potential dietary supplement to ameliorate neurodegenerative diseases.

Hydrazone- and imine-containing [PdPtL4]4+ cages: a comparative study of the stability and host-guest chemistry.

A new [PdPtL4]4+ heterobimetallic cage containing hydrazone linkages has been synthesised using the sub-component self-assembly approach. 1H and DOSY nuclear magnetic resonance (NMR) spectroscopy and electrospray ionisation mass spectrometry (ESIMS) data were consistent with the formation of the [PdPtL4]4+ architecture. The cage was stimulus-responsive and could be partially disassembled and reassembled by the addition of dimethylaminopyridine (DMAP) and p-tolenesulfonic acid (TsOH), respectively. Additionally, the stability of the hydrazone cage against hydrolysis in the presence of water and nucleophilic decomposition in the presence of guest molecules was compared to a previously synthesised imine-containing [PdPtL4]4+ cage. It was established that the hydrazone linkage was more resistant to hydrolysis. Furthermore, the host-guest (HG) chemistry with a series of drug and drug-like molecules was examined. The hydrazone cage was shown to interact with cisplatin while the smaller imine cage was shown to interact with 5-fluorouracil and oxaliplatin in CD3CN. No HG interactions were observed in the more polar d6-DMSO. In vitro antiproliferative activity studies demonstrated both cages were active against the cancer cell lines tested and displayed half-maximal inhibitory (IC50) values in the range of 25-35 μM. Most [PdPtL4]4+-drug mixtures tested had higher IC50 values than the hosts. However, the [PdPtL4]4+ cages, and [PdPtL4]4+:drug mixtures were less cytotoxic than the well established anticancer drugs cisplatin, oxaliplatin and 5-fluorouracil.

Sesquiterpenoids from Ixeris sonchifolia and their neuroprotective activities

The phytochemical investigation of the methanol extract of Ixeris sonchifolia led to the isolation and identification of nine analogs, including one new guaiane-type sesquiterpenoid, named ixerinoid A (1). The structure of 1 was determined by extensive analysis of the 1 D and 2 D nuclear magnetic resonance spectroscopic data, as well as quantum chemical calculations. Additionally, all the isolates were tested for their neuroprotective activity using the oxygen-glucose deprivation/reperfusion-induced SH-SY5Y cell injury model. Compounds 3, 5, 6, 8, and 9 displayed remarkable protective effects at concentrations of 1, 5, and 10 μM, respectively.

Antioxidant Phenylpropanoid Glycosides from Ginkgo biloba Fruit and Identification of a New Phenylpropanoid Glycoside, Ginkgopanoside.

Ginkgo biloba (Ginkgoaceae), well-known as the oldest living plant species and often referred to as a “living fossil,” is a famous medicinal plant that has been used in multiple countries to improve numerous illnesses, including anxiety, dementia, peripheral artery disease, and eye problems. We conducted a phytochemical exploration of G. biloba fruit, commonly consumed as a functional food as part of an ongoing natural product chemical research for the discovery of bioactive phytochemicals with novel structures. The natural product chemical analysis of the methanol extract of G. biloba fruit using column chromatography and high-performance liquid chromatography separation under the guidance of a liquid chromatography–mass spectrometry (LC/MS)-based analysis identified six phenylpropanoid glycosides (1–6), including one new compound, ginkgopanoside (1). The structures of the isolated compounds were elucidated by nuclear magnetic resonance spectroscopic data and LC/MS analysis, and the absolute configuration of compound 1 was established by chemical reactions followed by the application of Snatzke’s method. The 2,2-diphenyl-1-picrylhydrazyl (DPPH) scavenging activities of the isolated compounds 1–6 and the aglycone 1a of 1 were evaluated, and we found that compounds 1–5 exhibited antioxidant activities with IC50 values in the range 32.75–48.20 μM, while the aglycone 1a exhibited greater radical scavenging activity (IC50 = 5.23 μM) comparable to that of ascorbic acid (IC50 = 2.54 μM), a positive control, implying that the present of glucose may decrease the DPPH scavenging activity. These findings provide experimental information that the active phenylpropanoid glycosides could represent natural antioxidants for use in pharmaceuticals and functional foods.

Metabolomics analysis of the Finnish Geriatric Intervention Study to Prevent Cognitive Impairment and Disability (FINGER)

AbstractBackgroundThe Finnish Geriatric Intervention Study to Prevent Cognitive Impairment and Disability (FINGER) is a randomized controlled trial that showed significant benefits on cognition for a 2‐year multidomain lifestyle intervention vs regular health advice in 1260 at‐risk older individuals from the general population. The aim of this study was to investigate the metabolic effects of the intervention and their association with cognitive outcomes.MethodWe acquired metabolomics data of blood plasma on two time points (baseline and 2 years) in a set of 1089 participants (547 intervention and 542 control). A multi‐technology platform consisting of using ultra‐high performance liquid chromatography ‐ mass spectrometry (UHPLC‐MS) and 1H nuclear magnetic resonance spectroscopy (NMR) was used to generate extensive measurement coverage of the metabolome. The data was acquired using both reversed‐phase chromatography (RPC) tailored for the retention and separation of both complex and neutral lipids and hydrophilic interaction liquid chromatography (HILIC) for the retention and separation of small polar metabolites. The UHPLC‐MS untargeted data contains a total of 10,825 metabolomic features, 1244 of them currently annotated. The NMR data contains measurements of both small and macromolecules, including 112 lipoprotein fractions (derived using Bruker lipoprotein subclass analysis: BI‐LISA). Data analysis was conducted using linear mixed models.ResultSeveral baseline metabolite levels had a statistically significant association with cognition. Results will also be presented from ongoing analyses to investigate intervention effects on change in metabolites.ConclusionComplex metabolomics analyses are new in the context of multidomain lifestyle dementia prevention trials. While causality is yet to be investigated further, some of the metabolite classes and pathways observed (e.g. sphingolipids) have been previously implicated in cognitive decline and neurological disorders, suggesting early interpretable leads in the rich dataset at hand.

Two New Triterpenes from Basidiomata of the Medicinal and Edible Mushroom, Laetiporus sulphureus.

In the search for novel anti-infectives from natural sources, fungi, in particular basidiomycetes, have proven to still harbor so much potential in terms of secondary metabolites diversity. There have been numerous reports on isolating numerous secondary metabolites from genus Laetiporus. This study reports on two new triterpenoids, laetiporins C and D, and four known triterpenes from the fruiting body of L. sulphureus. The structures of the isolated compounds were elucidated based on their 1D and 2D nuclear magnetic resonance (NMR) spectroscopic data in combination with high-resolution electrospray mass spectrometric (HR-ESIMS) data. Laetiporin C exhibited weak antifungal activity against Mucor hiemalis. Furthermore, the compounds showed weak antiproliferative activity against the mouse fibroblast L929 and human cancer cell lines, including KB-3-1, A431, MCF-7, PC-3 and A549.

New Algorithm by Maximizing Mutual Information for Correction of Frequency Drifts Arising from One-Dimensional NMR Spectroscopic Data Acquisition.

Benchtop nuclear magnetic resonance (NMR) instruments are getting popular these days. However, the obtained spectra sometimes suffer from significant frequency drifts, which cause difficulty in accumulating the raw data. In this paper, a new algorithm for correction of frequency drifts is proposed, which operates by maximizing mutual information between the obtained spectroscopic data. The algorithm worked well for both 1H and 19F NMR spectroscopic data, even in the case of very noisy ones. In comparison with the previously reported algorithms, the present algorithm has an advantage that NMR spectra complicated by signal overlapping and spin coupling can be handled without difficulty. This makes the present algorithm particularly advantageous for application of benchtop NMR spectrometers in organic chemistry.

Untargeted Metabolome- and Transcriptome-Wide Association Study Suggests Causal Genes Modulating Metabolite Concentrations in Urine.

Gene products can affect the concentrations of small molecules (aka “metabolites”), and conversely, some metabolites can modulate the concentrations of gene transcripts. While many specific instances of this interplay have been revealed, a global approach to systematically uncover human gene-metabolite interactions is still lacking. We performed a metabolome- and transcriptome-wide association study to identify genes influencing the human metabolome using untargeted metabolome features, extracted from 1H nuclear magnetic resonance spectroscopy (NMR) of urine samples, and gene expression levels, quantified from RNA-Seq of lymphoblastoid cell lines (LCL) from 555 healthy individuals. We identified 20 study-wide significant associations corresponding to 15 genes, of which 5 associations (with 2 genes) were confirmed with follow-up NMR data. Using metabomatching, we identified the metabolites corresponding to metabolome features associated with the genes, namely, N-acetylated compounds with ALMS1 and trimethylamine (TMA) with HPS1. Finally, Mendelian randomization analysis supported a potential causal link between the expression of genes in both the ALMS1- and HPS1-loci and their associated metabolite concentrations. In the case of HPS1, we additionally observed that TMA concentration likely exhibits a reverse causal effect on HPS1 expression levels, indicating a negative feedback loop. Our study highlights how the integration of metabolomics, gene expression, and genetic data can pinpoint causal genes modulating metabolite concentrations.