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At least 19 recordsLinked to original sources
PubMed2025

MEANtools integrates multi-omics data to identify metabolites and predict biosynthetic pathways.

During evolution, plants have developed the ability to produce a vast array of specialized metabolites, which play crucial roles in helping plants adapt to different environmental niches. However, their biosynthetic pathways remain largely elusive. In the past decades, increasing numbers of plant biosynthetic pathways have been elucidated based on approaches utilizing genomics, transcriptomics, and metabolomics. These efforts, however, are limited by the fact that they typically adopt a target-based approach, requiring prior knowledge. Here, we present MEANtools, a systematic and unsupervised computational integrative omics workflow to predict candidate metabolic pathways de novo by leveraging knowledge of general reaction rules and metabolic structures stored in public databases. In our approach, possible connections between metabolites and transcripts that show correlated abundance across samples are identified using reaction rules linked to the transcript-encoded enzyme families. MEANtools thus assesses whether these reactions can connect transcript-correlated mass features within a candidate metabolic pathway. We validate MEANtools using a paired transcriptomic-metabolomic dataset recently generated to reconstruct the falcarindiol biosynthetic pathway in tomato. MEANtools correctly anticipated five out of seven steps of the characterized pathway and also identified other candidate pathways involved in specialized metabolism, which demonstrates its potential for hypothesis generation. Altogether, MEANtools represents a significant advancement to integrate multi-omics data for the elucidation of biochemical pathways in plants and beyond.

Metabolomics↗
PubMed2026

Identification and Catalytic Optimization of Pinene Oxidases in Paeoniflorin Biosynthetic Pathway.

Paeoniflorin is a pharmacologically important cage-like monoterpene glycoside characteristic of Paeonia plants, yet its biosynthetic pathway has remained largely unresolved, hindering sustainable production. Here, we confirmed that paeoniflorin biosynthesis originates from α-pinene and identified three novel cytochrome P450 enzymes that catalyze pinene oxidation. CYP71AN126 catalyzes the hydroxylation of α-pinene at positions C4 and C10, followed by further oxidation of the alcohol to a ketone at C4, whereas CYP76A225/226 exclusively catalyze C10 hydroxylation. Virus-induced gene silencing (VIGS) assays demonstrated that silencing CYP71AN126, but not CYP76A225 and CYP76A226, significantly reduced the paeoniflorin content, indicating that C4 hydroxylation plays an important role in paeoniflorin biosynthesis, whereas C10 hydroxylation is not. Through the analysis of natural sequence and activity divergence among CYP71AN126 and CYP76A225/226, combined with protein structure prediction and site-directed mutagenesis, we identified L493 as a critical residue involved in regulating catalytic site specificity and substrate specificity of CYP71AN126. Mutation of L493 reduced or eliminated the formation of undesired C10 hydroxylation side-product and enhanced substrate specificity. These findings establish C4 oxidation of α-pinene as the critical committed step in paeoniflorin biosynthesis. Our study lays a foundation for elucidating the complete biosynthetic pathway of paeoniflorin in Paeonia and provides a target for enzyme engineering of CYP71AN126 aimed at the efficient production of paeoniflorin via synthetic biology approaches.

Paeonia genus↗
PubMed2026

Structural characterization and predicted biosynthetic pathway of the polysaccharide component of bioflocculant from starch-degrading Bacillus subtilis ZHX3.

Polysaccharides-based bioflocculant is a promising eco-friendly alternative to conventional flocculants, yet their application is limited by high production cost. Understanding the biosynthetic pathway is essential for targeted strain improvement. In this study, we characterized polysaccharides structure of bioflocculant MBF-ZHX3 from Bacillus subtilis ZHX3 and predicted its biosynthetic pathway via genomic analysis combined with quantitative real-time PCR (qPCR). Two purified polysaccharide fractions, PS1-1 (5982 Da) and PS2-1 (17,577 Da), were obtained. Both were mainly composed of glucose, with a backbone of →4)-α-D-Glcp-(1 → and α-D-Glcp-(1 → branches attached at O-6. Whole-genome sequencing revealed a circular chromosome of 4,122,369 bp and two plasmids. Functional annotation showed high carbohydrate metabolism activity, with 284 genes (9.52%) and 264 genes (11.28%) assigned to carbohydrate metabolism in the COG and KEGG database, respectively. A complete eps gene cluster consisting of 15 open reading frames was identified. qPCR showed that key genes involved in substrate uptake (ptsG, malP, mdxEFG-msmX) and nucleotide sugar synthesis (pgcA, gtaB) were significantly upregulated. The priming glycosyltransferase (GT) epsL and the primary GT epsF were upregulated, along with the flippase epsK, polymerase epsG, and chain-length regulators epsA and epsB. Based on these findings, we propose a putative biosynthetic pathway for the polysaccharide component of MBF-ZHX3, and identify epsL, epsF, and epsG as prioritized targets for future genetic engineering. This work provides an integrated structural-genomic-transcriptomic framework that can guide rational strain improvement to enhance bioflocculant production.

Polysaccharides structure↗
PubMed1976

Immunological cross reactivity of four enzymes involved in the biosynthetic pathway of lysine, methionine and threonine in Escherichia coli K12.

In Escherichia coli K12 the biosynthetic pathway of lysine, methionine and threonine is characterized by three isofunctional aspartokinases and two homoserine dehydrogenases. A single polypeptide chain carries the threonine-sensitive aspartokinase and homoserine dehydrogenase (AK I-HDH I), and a different polypeptide chain carries the methionine-repressible aspartokinase and homoserine dehydrogenase (AK II-HDH II). Immuno-adsorbants prepared with rabbit antibodies against AK I-HDH I bind the lysine-sensitive aspartokinase (AK III), the AK II-HDH II, and the homoserine kinase (HSK), an enzyme of the threonine biosynthetic pathway. Saturation of the immunoadsorbant with AK I-HDH I results in a decreased binding capacity for the other enzymes. Displacement of bound AK III or HSK can be obtained with pure AK I-HDH I, showing that the affinity of the antibodies to homologous antigens is higher than to heterologous ones. Immunoadsorbants prepared with anti-HSK antibodies show the same type of recognition: binding of the three aspartkinases and a capacity to displace the heterologous antigens bound. Accordingly, the same antibodies, implicated in the binding of the homologous antigen, bind the other enzymes. None of the other enzymes of the pathway, or the other kinases tested are recognized by the two immunoadsorbants. It can be postulated that in E. coli K12, duplication of a common ancestor gene gave rise to the three aspartokinases and to the homoserine kinase; two of the genes coding for the aspartokinases fused with those coding for the homoserine dehydrogenases. Indicating that only few epitopes are shared by these enzymes, by conventional immuno-diffusion techniques no precipitation lines appeared with antibodies against AK I-HDH I and the other proteins.

Alcohol Oxidoreductases↗
PubMed2026

A chromosome-level genome assembly of Lycoris radiata reveals the evolutionary origin of Amaryllidaceae alkaloids and elucidates the complete galanthamine biosynthetic pathway.

Amaryllidaceae alkaloids (AmAs) comprise a structurally diverse group of specialized metabolites produced almost exclusively by species of the Amaryllidoideae subfamily and are of substantial pharmacological importance. However, the limited availability of high-quality genomes from Amaryllidoideae plants has constrained systematic investigations of the genes and evolutionary processes underlying AmA biosynthesis. Here, we present a chromosome-level genome assembly of Lycoris radiata, which enabled the discovery of key downstream enzymes in the galanthamine biosynthetic pathway and uncovered reversible reactions between two critical metabolite pairs. These findings provide new mechanistic insight into pathway architecture and enable reconstruction of the galanthamine biosynthetic pathway in Yarrowia lipolytica. Comparative genomic analyses indicate that several core genes for AmA biosynthesis originated in ancestral angiosperms, whereas the complete pathway was likely assembled in the Amaryllidoideae subfamily through gene duplication and neofunctionalization. Furthermore, integrated metabolomic and transcriptomic analyses suggest that roots contribute actively to AmA metabolism in Lycoris. Together, these findings provide a genomic and biochemical framework for understanding the evolution and engineering of AmA biosynthesis.

Lycoris↗
PubMed2025

The Biosynthetic Pathway to the Pyrroloiminoquinone Marine Natural Product Ammosamide C.

Ammosamide C is a marine natural product containing a highly decorated pyrroloiminoquinone core. Studies on the biosynthetic gene cluster (BGC) that produces ammosamides previously revealed that they are made by a series of posttranslational modifications (PTMs). The BGC includes genes encoding a precursor peptide AmmA and four enzymes known as PEptide Aminoacyl-tRNA Ligases (PEARLs). Initial studies into the ammosamide biosynthetic pathway demonstrated Trp addition to a precursor peptide by the PEARL AmmB2. Thereafter, sequential modifications by several enzymes, including two other PEARLs lead to the formation of a peptide intermediate bearing a C-terminal diaminoquinone. In the present work, we present the biosynthetic steps that convert this intermediate to ammosamide C. The PEARL AmmB4 unexpectedly appends an arginine to the C-terminus of the aforementioned intermediate. Then, C-terminal proteolysis by the heterodimeric TldD/E-like protease Amm12/13 releases a dipeptide, which is subsequently cleaved by the dipeptidase Amm19 to produce a Trp-derived diaminoquinone. Amm3 next catalyzes the conversion of this Trp derivative to the corresponding chlorinated ammosamaic acid. Finally, a putative aminotransferase Amm20 performs an amidation, and Amm23 methylates this intermediate to arrive at ammosamide C; the order of these last two steps could not be determined definitively. This study reveals an unexpectedly lengthy route to ammosamide that illustrates the opportunistic nature of natural product biosynthesis, demonstrates a role for a PEARL that is unlike previous roles, identifies steps that are not PTMs, and adds Arg-tRNA to the growing repertoire of aminoacyl tRNAs that are used by PEARLs.

Biological Products↗
PubMed1977

Repression of the tyrosine, lysine, and methionine biosynthetic pathways in a hisT mutant of Salmonella typhimurium.

A comparison was made of the repressibility of certain enzymes in the tyrosine, methionine, and lysine biosynthetic pathways in wild-type Salmonella typhimurium and a hisT mutant. The results show that (i) tyrosine represses the synthesis of the tyrosine-sensitive 3-deoxy-D-arabino-heptulsonic acid 7-phosphate synthetase and the tyrosine aminotransferase to the same extent in a hisT mutant as in wild type and (ii) there is no detectable alteration in the extent to which methionine represses O-succinylhomoserine synthetase or in the extent to which lysine represses the lysine-sensitive beta-aspartokinase as a result of the hisT mutation.

2-Isopropylmalate Synthase↗
PubMed1975

Evolution of biosynthetic pathways: immunological approach.

Through the use of specific immunoadsorbent columns, it is shown that Escherichia coli aspartokinase I-homoserine dehydrogenase I, aspartokinase II-homoserine dehydrogenase II, aspartokinase III, and homoserine kinase, enzymes involved in the same complex biosynthetic pathway, share antigenic determinants. This raises the question of a common origin for the four cibtenoirart kinases. (Aspartate kinase or ATP:L aspartate 4-phosphotransferase, EC 2.7.2.4; homoserine dehydrogenase or Lhomoserine:NADP oxidoreductase, EC 1.1.1.3; homoserine kinase or ATP:L-homoserine O-phosphotransferase, EC 2.7.1.39.)

Alcohol Oxidoreductases↗
PubMed1977

The immediate nucleotide precursor, guanosine triphosphate, in the riboflavin biosynthetic pathway.

In the present paper, the nucleotide precursor of riboflavin was investigated by experiments with labeled purines using non-growing cells of Eremothecium ashybii. The added purines, at 10(-4) M, were effectively incorporated into riboflavin at an early stage of riboflavin biosynthesis under the experimental conditions. In particular, both labeled xanthine and labeled guanine were specifically transported to guanosine nucleotides, GMP, GDP, GDP-Mannose and GTP, in the course of the riboflavin biosynthesis. A comparison of specific activities of labeled guanosine nucleotides and labeled riboflavin indicated that the nucleotide precursor of riboflavin is guanosine triphosphate. From the results obtained, a biosynthetic pathway of riboflavin is proposed under "DISCUSSION."

Ascomycota↗
PubMed2026

Enzymatic innovations in Angelica pubescens reveal dual coumarin biosynthetic pathways driving metabolic diversification.

Coumarins are structurally diverse phenylpropanoid derivatives with ecological and pharmacological significance, yet the biosynthetic logic underlying their diversification remains incompletely understood in non-model medicinal plants. Angelica pubescens (Apiaceae), widely used in traditional Chinese medicine, accumulates a rich repertoire of furanocoumarins and dihydrofuranocoumarins, making it an ideal system to investigate this metabolic complexity. Here, we combined chromosome-level genome assembly, transcriptome and metabolite profiling, phylogenetics, and heterologous expression assays to dissect coumarin biosynthesis in A. pubescens. We identified two functionally specialized O-methyltransferases, ApOMT1 and ApOMT2, which catalyze regioselective methylation of xanthotoxol and bergaptol to yield the furanocoumarins xanthotoxin and bergapten. We also characterized ApCYP736A121, a cytochrome P450 enzyme that converts osthenol to the dihydrofuranocoumarin columbianetin via a previously unknown mechanism. Gene expression and metabolite accumulation patterns across tissues and developmental stages revealed functional partitioning among pathway branches. Phylogenetic and syntenic analyses indicated that ApOMT1 and ApOMT2 arose through subfunctionalization following gene duplication, whereas ApCYP736A121 evolved via neofunctionalization from a distantly related CYP736 ancestor. Together, our findings uncover dual biosynthetic routes to structurally distinct coumarins in A. pubescens and provide insights into the evolutionary mechanisms contributing to metabolic innovation in Apiaceae. This work lays a foundation for future efforts to engineer coumarin pathways and understand their ecological functions in medicinal plants.

Coumarins↗
PubMed1978

Regulation of enzyme synthesis in the arginine biosynthetic pathway of Pseudomonas aeruginosa.

In Pseudomonas aeruginosa the synthesis of only two out of eight arginine biosynthetic enzymes tested was regulated. Comparisons were made between the specific activities of these enzymes in bacteria grown on arginine or on its precursor, glutamate. N2-Acetylornithine 5-aminotransferase (ACOAT), an enzyme involved in both the biosynthesis and catabolism of arginine, was induced about 14-fold during growth of the organism on arginine as the only carbon and nitrogen source, and the anabolic ornithine carbamoyltransferase (aOTC), a strictly biosynthetic enzyme, was repressed 18-fold. Addition of various carbon sources to the arginine medium led to repression of ACOAT and to derepression of aOTC. Fructose, which supported only slow growth of P. aeruginosa, had a weak regulatory effect on the synthesis of the two arginine enzymes while citrate, a good carbon source for this organism, had a strong effect. The repression of ACOAT by citrate was not relieved by adding cyclic AMP to the medium. Under a variety of growth conditions leading to different enzyme activities, a linear relationship between the reciprocal of the specific activity of ACOAT and the specific activity of aOTC was observed. This inverse regulation of the formation of the two enzymes suggested that a single regulatory system governs their synthesis. Such a view was supported by the isolation of citrate-resistant regulatory mutants which constitutively formed ACOAT at the induced level and aOTC at the repressed level.

Arginine↗
PubMed1975

Pyrimidine biosynthetic pathway of Baccillus subtilis.

Biochemical and genetic data were obtained from a series of 51 Pyr- strains of Bacillus subtilis. The observed enzymatic deficiencies allowed the mutants to be placed into 12 clases, some of which represent defects in more than one of the six known pyrimidine biosynthetic enzymes. Mapping analysis by transformation has shown that all the Pyr- mutations are located in a single small area of the B. subtilis genome. A correlation of the biochemical defects and the genetic data has been made. Those mutations conferring similar enzymatic deficiencies were found to be contiguous on the B. subtilis map. Regulatory aspects of the pyrimidine pathway have also been investigated and are compared to previously reported results from other organisms. Evidence is presented which bears upon the possible physical association of the first three enzymes and the association of at least some of the enzymes of this pathway with particulate elements of the cell. A model for the organization of the enzymes is presented with dihydroorotate dehydrogenase as the central enzyme in a proposed aggregate.

Aspartate Carbamoyltransferase↗
PubMed1976

Selective hypoaldosteronism: a study of steroid biosynthetic pathways under adrenocorticotrophin and angiotensin II infusion.

1. The functional integrity of the adrenal cortex has been tested in a case of selective hypoaldosteronism by adrenocorticotrophin (ACTH) and angiotensin II (AII) infusion. 2. During ACTH infusion a normal functioning zona fasciculata was indicated by the impressive increase of the ACTH-dependent plasma steroids; the aldosterone response was moderate. 3. During AII infusion the plasma aldosterone response was blunted with an unexpected dose-dependent increase in pregnenolone, resulting in abnormal decreasing progesterone/pregnenolone ratios during the infusion, suggesting a slow-down in the conversion of pregnenolone into progesterone. 4. This defect, a probable consequence of chronic renin deficiency on the zona glomerulosa, could be a contributing factor to the hypoaldosteronism.

Adrenal Cortex↗
PubMed1979

Probable biosynthetic pathway for the synthesis of the B antigen for Bh variants.

Red cells and serum from two Bh variants (B+H-cells) have been investigated for B and H blood group glycosyltransferases. The H enzyme could not be detected using either type 1 or type 2 chain acceptors. The B enzyme was present in normal amount when 2'-fucosyllactose was used as substrate, neither 6'-fucosyllactose nor 6'-fucosyllactosamine could act as acceptors for the B enzyme. Upon treatment of the Bh red cells by the B-degrading enzyme from Trichomonas foetus the B antigen was destroyed while H determinants were uncovered (B-H + cells). The cells thus treated could be further converted into A&H-red cells by the action of the A transferase from human blood group A serum. Previous treatment of the B-H + cells by the H-degrading enzyme from T. foetus, however, led to B-/-erythrocytes and prevented their conversion into A red blood cells by the A enzyme. The results clearly demonstrate that, as found in normal B individuals, the B antigen from Bh cells is built up from the H precursor and provide additional evidence that H is not a completely silent gene in Bh individuals.

ABO Blood-Group System↗
PubMed1975

Organization and control in the arginine biosynthetic pathway of Neurospora.

Eight enzymes involved in the conversion of acetylglutamate to arginine in Neurospora crassa were studied. The data indicate that of three enzymes early in the sequence, only the first, acetylglutamate kinase, is a nonorganellar enzyme. The next two, N-acetyl-gamma-glutamyl-phosphate reductase and acetylornithine aminotransferase, are in the mitochondrion, which was previously shown to contain the subsequent enzymes: acetylornithine-glutamate acetyltransferase, ornithine carbamyltransferase, and carbamyl-phosphate synthetase A (arginine specific). The last two enzymes of the pathway, argininosuccinate synthetase and argininosuccinate lyase, were previously shown to be cytosolic. All enzymes but one have low amplitudes or repression. Their levels respond little to arginine excess and are about twofold elevated (threefold for ornithine carbamyltransferase) as a result of arginine limitation in the arg-12-8 strain. No restriction of the incorporation of mitochondrial enzymes into mitochondria could be detected when the levels of these enzymes were elevated. Two enzymes, acetylglutamate kinase and carbamyl-phosphate synthetase A, which initiate the synthesis of the ornithine and guanidino moieties of arginine, respectively, show the lowest specific activities in crude extract. These enzymes display special regulatroy features. Acetylglutamate kinase, which has a typically low amplitude of repression, is subject to feedback inhibition. Carbamyl-phosphate synthetase A is wholly insensitive to arginine or citrulline in vitro or in vivo, but displays a very large amplitude of repression (about 60-fold). It is unique in that it can be almost completely repressed by growth of mycelia in excess arginine. These data suggest that mitochondrial localization may be incompatible with a mechanism of feedback inhibition by a cytosolic effector, arginine. Further, they suggest that the high repressibility of carbamyl-phosphate synthetase A compensates for its feedback insensitivity.

Acetyltransferases↗