Abstract
Biotin is an essential cofactor for multiple metabolic reactions catalyzed by carboxylases. Biotin is covalently linked to apoproteins by holocarboxylase synthetase (HCS). Accordingly, some mutations in HCS cause holocarboxylase deficiency, a rare metabolic disorder that can be life-threatening if left untreated. However, the long-term effects of HCS deficiency are poorly understood. Here, we report our investigations of bpl-1, which encodes the Caenorhabditis elegans ortholog of HCS. We found that mutations in the biotin-binding region of bpl-1 are maternal-effect lethal and cause defects in embryonic polarity establishment, meiosis, and the integrity of the eggshell permeability barrier. We confirmed that BPL-1 biotinylates four carboxylase enzymes, and we demonstrate that BPL-1 is required for efficient de novo fatty acid biosynthesis. We also show that the lack of larval growth defects as well as nearly normal fatty acid composition in young adult worms is due to sufficient fatty acid precursors provided by dietary bacteria. However, BPL-1 disruption strongly decreased levels of polyunsaturated fatty acids in embryos produced by bpl-1 mutant hermaphrodites, revealing a critical role for BPL-1 in lipid biosynthesis during embryogenesis and demonstrating that dietary fatty acids and lipid precursors are not adequate to support early embryogenesis in the absence of BPL-1. Our findings highlight that studying BPL-1 function in C. elegans could help dissect the roles of this important metabolic enzyme under different environmental and dietary conditions.
Highlights
Biotin is an essential cofactor for multiple metabolic reactions catalyzed by carboxylases
We confirmed that BPL-1 biotinylates four carboxylase enzymes, and we demonstrate that BPL-1 is required for efficient de novo fatty acid biosynthesis
Wild-type worms significantly increased de novo fat synthesis in response to the L8 diet (Fig. 5D), suggesting that the worms can detect dietary malonate and other fatty acid precursors and increase de novo synthesis to compensate when these dietary substrates are limited. These data indicate that C. elegans maintains a balance of malonate or other precursors obtained from the diet and malonyl-CoA synthesized de novo from acetyl-CoA to support lipid synthesis for larval growth and development but that dietary lipids and precursors are not available or are not utilized during oogenesis and embryogenesis, and de novo synthesized lipids are required at this stage (Fig. 5, E and F)
Summary
To test whether any of the embryonic defects observed in bpl-1 were caused by loss of embryonic PUFAs, we examined mutants in the PUFA biosynthesis pathway. Wild-type worms significantly increased de novo fat synthesis in response to the L8 diet (Fig. 5D), suggesting that the worms can detect dietary malonate and other fatty acid precursors and increase de novo synthesis to compensate when these dietary substrates are limited Together, these data indicate that C. elegans maintains a balance of malonate or other precursors obtained from the diet and malonyl-CoA synthesized de novo from acetyl-CoA to support lipid synthesis for larval growth and development but that dietary lipids and precursors are not available or are not utilized during oogenesis and embryogenesis, and de novo synthesized lipids are required at this stage (Fig. 5, E and F)
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