J Biol Chem. 2026 Sep 8:113545. doi: 10.1016/j.jbc.2026.113545. Online ahead of print.
ABSTRACT
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.
PMID:42710669 | DOI:10.1016/j.jbc.2026.113545
