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PubMed2024

Novel pathogenic variant in a mild case of type B molybdenum cofactor deficiency: case report and literature review.

BACKGROUND: Molybdenum cofactor deficiency (MoCD) is a rare metabolic disorder caused by pathogenic variants in the highly conserved biosynthetic pathway of molybdenum cofactor (MoCo), resulting in sulfite intoxication. MoCD may present in a clinically severe, fatal form marked by intractable seizures after birth, hyperekplexia, microcephaly and cerebral atrophy, or a later onset form with a more varied clinical course. Three types of MoCD have been described based on the effected gene along the MoCo synthesis pathway: type A (MOCS1); type B (MOCS2 or MOCS3) and type C (GPHN). The MOCS2 gene is bicistronic, encoding the small (MOCS2A) and large (MOCS2B) subunits with an overlapping coding region. This case report describes a patient with the first known variant causative of mild disease in the overlapping bicistronic region (c.263 G > C) and the first ever described in the highly conserved C-terminal glycine-glycine motif of MOCS2A. CASE PRESENTATION: The patient developed normally until age 12 months when she presented in the setting of acute illness with developmental regression, low serum uric acid, and MRI with bilateral globus pallidus (GP) injury. Exome sequencing identified a homozygous variant of unknown significance in the MOCS2 gene and the diagnosis of MoCD type B was confirmed by the patient's low serum uric acid coupled with elevated urine sulfocysteine and associated metabolites, resulting in gene reclassification. Nearly four years after her initial presentation she has demonstrated progress in language and motor domains, consistent with a mild phenotype of MoCD. CONCLUSIONS: The case emphasizes challenges in identifying atypical forms of rare diseases, the importance of exome sequencing to identify mild cases of MoCD, and the ongoing challenges with understanding the MOCS2 gene. While one FDA approved treatment exists for MoCD type A, further research into the mechanisms of phenotype-genotype differences among this patient population may aid in additional therapeutic options for MoCD.

Female↗

PubMed2026

Quantitative proteomics of molybdenum cofactor biosynthesis and utilization in Caenorhabditis elegans.

The molybdenum cofactor (Moco) is a chemically labile prosthetic group required by a small but essential set of metazoan enzymes, including sulfite oxidase, xanthine dehydrogenase, aldehyde oxidases, and the mitochondrial amidoxime reducing components (MARC). Disruption of Moco biosynthesis in humans causes Molybdenum Cofactor Deficiency (MoCD), a severe neonatal encephalopathy. Caenorhabditis elegans is unique among animals studied so far in that it can meet its Moco requirement through both endogenous biosynthesis and direct uptake of mature Moco from its bacterial diet. However, the organism-wide abundance of the Moco biosynthetic machinery and Moco-dependent enzymes, and their response to altered Moco supply, have remained unknown. Here, using data independent acquisition proteomics with histone anchored absolute quantification, we generated an organism wide quantitative atlas of Moco biosynthesis and utilization in C. elegans under standard and Moco limiting conditions. Components of the biosynthetic pathway showed a strikingly asymmetric abundance. The mitochondrial enzyme MOC-5, which catalyzes the first committed step in Moco biosynthesis, was present at only about 120 copies per genome equivalent, roughly fifty-fold below the downstream cytoplasmic biosynthetic machinery, which ranged from about 5,000 to 8,500 copies per genome equivalent, identifying MOC-5 as a stoichiometric bottleneck. On the utilization side, the MARC paralogs were the dominant Moco consumers, with MARC-1 exceeding 20,000 copies per genome equivalent. Loss of dietary or endogenous Moco selectively depleted the nonsulfurated clients SUOX-1 and MARC-1, whereas biosynthetic proteins remained unchanged, indicating that protein stability, rather than compensatory expression, is the main response to Moco limitation.

Caenorhabditis elegans↗

PubMed2024

The parasitic nematode Haemonchus contortus lacks molybdenum cofactor synthesis, leading to sulphite sensitivity and lethality in vitro.

Sulphite oxidase has an essential role in detoxifying environmental and endogenously generated sulphite into sulphate and requires the molybdenum cofactor (Moco) to function. Until recently it was believed that the synthesis pathway for Moco was so important for survival that it was conserved in all multicellular animals. Here we report the use of comparative genomics to identify the absence of the first enzyme involved in Moco synthesis in Haemonchus contortus, a highly pathogenic and economically important helminth of livestock that, similar to many parasitic nematode species, has proved difficult to maintain in vitro. We show that Moco deficiency in Haemonchus leads to a high sensitivity to environmental sulphite and limits the ability to maintain the early parasitic larval stages in vitro. Analogous losses in Moco synthesis in other recently sequenced nematode species are also identified. These findings may lead to improved culture methods for parasitic nematodes and to novel approaches for their control.

Animals↗

PubMed2026

Genome mining of alkaliphilic cyanobacterial consortia: identification of biosynthetic gene clusters in Sodalinema and associated heterotrophs.

Alkaline soda lakes are high-pH environments that host specialized microbial communities with potential for biotechnology and natural product discovery. We characterized three Sodalinema-dominated cyanobacterial consortia enriched from Canadian soda lakes over 510 days. Using hybrid metagenomic sequencing and metatranscriptomics across pH, alkalinity, and temperature gradients, we reconstructed high-quality metagenome-assembled genomes and assessed functional activity. All consortia converged toward cyanobacteria dominance and exhibited temperature optima between 21°C and 30°C. Phylogenetic analysis placed Sodalinema genomes within a distinct clade affiliated with Candidatus Sodalinema alkaliphilum. Genomic analysis indicated complete biosynthetic pathways for vitamin B5, vitamin B7, and the molybdenum cofactor, but incomplete pathways for vitamins B1, B9, and B12, consistent with patterns observed in Sodalinema yuhuli. Metatranscriptomic profiles showed increased expression of genes involved in phycocyanin and carotenoid biosynthesis at pH 10.2 relative to pH 8.5. Biosynthetic gene cluster analysis revealed that most secondary metabolic potential resided in heterotrophic community members. Roseinatronobacter encoded pathways for N-acyl homoserine lactones, osmoprotectants, betalactones, and prodigiosin, while Alkalimonas, Wenzhouxiangella, and members of the Kiloniellales encoded clusters for lanthipeptides, cyclodipeptides, hydrogen cyanide, and pyrroloquinoline quinone. These findings indicate functional partitioning within the consortia and highlight the contribution of heterotrophs to secondary metabolism.IMPORTANCEAlkaline soda lakes contain microbial communities adapted to high pH that remain underexplored for biotechnology. This study focuses on Sodalinema, a filamentous cyanobacterium that dominates enriched consortia from Canadian soda lakes, and its associated heterotrophic partners. We show that while Sodalinema drives primary productivity, heterotrophic bacteria encode most of the pathways for antimicrobial and signaling compounds. These interactions may support community stability and defense against competing microorganisms. By linking genomic potential with gene expression, this work identifies alkaline cyanobacterial consortia as a source of bioactive compounds and provides a framework for exploring extremophilic microbial communities for natural product discovery.

Sodalinema↗

PubMed2026

Salmonella uses sulfate reductases with unique catalytic activity to promote gut colonization in mice.

Non-typhoidal Salmonella use molybdenum cofactor-containing MopB- or DMSO reductase-family members to respire chemically diverse substrates, including formate, nitrate and methionine sulfoxide, during infection. The DmsABC enzymatic complex encodes one such DMSO reductase to promote oxidative stress resistance. The Salmonella genome encodes several gene paralogues but their role in virulence is unclear. Here we characterize three Salmonella MopB-family extracytoplasmic sulfate reductases, which we call Xsr1A, Xsr2A and Xsr3A. Infection experiments in mice and macrophages show that these sulfate reductases support Salmonella growth and virulence in the gut and during systemic infection, countering the oxidative effects of host respiratory burst activity. Further experiments show that they are molybdenum cofactor-independent enzymes, and instead depend on the nearby redox-active [4Fe-4S] prosthetic group for catalytic activity. Orthologues of these sulfate reductases were found across distant evolutionary branches, suggesting that [4Fe-4S]-dependent catalysis may occur across the ubiquitous MopB superfamily. Our findings offer insights into the modular evolution of redox centres in the widespread MopB superfamily.

Animals↗

PubMed2026

Unraveling anaerobic indole degradation in an acclimated sludge consortium: Candidate pathways and microbial division of labor inferred from metagenomic and metatranscriptomic analyses.

Indole is a widespread nitrogen-containing heterocyclic compound in manure, sludge, and wastewater systems, yet the enzymes and microbial populations involved in its anaerobic transformation remain poorly resolved. Here, we established a long-term acclimated anaerobic sludge consortium and combined degradation assays, metabolite profiling, metatranscriptomics, and genome-resolved metagenomics to investigate the functional basis of anaerobic indole degradation. After 120 days of acclimation, the consortium stably degraded 100 mg/L indole, whereas skatole was not effectively removed under the same strategy, indicating substrate-specific adaptation of the microbial community. Metabolite profiling detected oxindole, dioxindole, isatin, and anthranilic acid, supporting a putative transformation route involving pyrrole-ring oxidation and ring cleavage toward anthranilate-like intermediates. Metatranscriptomic analysis identified 16,660 differentially expressed genes after indole addition, with strong transcriptional responses involving oxidoreductases, hydrolases, cofactor-dependent redox metabolism, aromatic-CoA-related metabolism, and methane metabolism-associated pathways. Transcriptional responses highlighted the xanthine dehydrogenase-like molybdenum-enzyme system and isatin hydrolase as candidate contributors to upstream indole transformation, whereas those of abmG-like, bcrC, and oah genes were consistent with possible anthranilic acid activation and downstream CoA-type processing. MAG-resolved analysis further suggested that these candidate functions may be distributed among populations affiliated with Bacteroidota, Chloroflexota, Desulfobacterota, and Methanobacterium. Together, these findings establish a stable anaerobic indole-degrading consortium and provide a testable functional framework for syntrophic interactions linking upstream indole transformation, aromatic-CoA metabolism, and methanogenesis-associated carbon flow.

Anaerobic degradation↗