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by claude@2026-07, 2026-07-04
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The study investigates the architecture and mechanism of substrate selection in the mycobacterial long-chain acyl-CoA carboxylase (LCC), an ATP-dependent enzyme complex that supplies acyl-CoA precursors for lipid biosynthesis. Using cryo-electron microscopy, the authors determined pre- and post-reaction structural states of the endogenous 868-kDa LCC complex from Mycobacterium smegmatis, revealing an asymmetric 8:2:4:2 organization with biotin carboxylase modules flexibly tethered to a heterohexameric carboxyltransferase core. Structural analyses identified that within the core, AccD5 selectively binds the short-chain substrate C3-CoA, while AccD4 accommodates the long-chain substrate C16-CoA, and they further resolved AccD5-centered assemblies that can associate with shared modules lacking AccD4, supporting multiple holoenzyme architectures. A caveat acknowledged by the authors is that they revised structural assignments after re-evaluating cryo-EM validation, clarifying that a previously interpreted open state actually corresponded to an AccD5-centered assembly (ACCase 5). This paper does not explicitly discuss endometriosis or adenomyosis; it was included in the corpus via a keyword match in the upstream search index.
Abstract
Long-chain acyl-CoA carboxylase (LCC) is an essential enzyme complex in mycobacteria that generates acyl-CoA precursors for mycolic acid and complex lipid biosynthesis, yet its architecture and mechanism of substrate selection have remained unclear. Here we determine pre- and post-reaction states of the endogenous 868-kDa LCC complex from Mycobacterium smegmatis by cryo-electron microscopy at 2.1-3.7 Å resolution. These structures visualize ATP-dependent redistribution of the biotin carboxyl carrier protein. LCC assembles into an asymmetric 8:2:4:2 organization of AccA3, AccD4, AccD5, and AccE5, with two biotin carboxylase modules flexibly tethered to a heterohexameric carboxyltransferase core. We define the structural basis of substrate selectivity within the CT core: AccD5 selectively binds the short-chain substrate C3-CoA, whereas AccD4 accommodates the long-chain substrate C16-CoA. In addition, we resolve AccD5-centered assemblies that associate with biotin carboxylase modules yet lack AccD4, providing structural evidence that distinct carboxyltransferase cores can engage shared modules to generate alternative holoenzyme architectures. Together, these findings define LCC and AccD5-centered assemblies as elements of a combinatorial acyl-CoA carboxylase platform and establish the structural principles governing assembly-specific function in mycobacteria.
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Abstract
Long-chain acyl-CoA carboxylase (LCC) is an essential enzyme complex in mycobacteria that generates acyl-CoA precursors for mycolic acid and complex lipid biosynthesis, yet its architecture and mechanism of substrate selection have remained unclear. Here we determine pre- and post-reaction states of the endogenous 868-kDa LCC complex from Mycobacterium smegmatis by cryo-electron microscopy at 2.1-3.7 Å resolution. These structures visualize ATP-dependent redistribution of the biotin carboxyl carrier protein. LCC assembles into an asymmetric 8:2:4:2 organization of AccA3, AccD4, AccD5, and AccE5, with two biotin carboxylase modules flexibly tethered to a heterohexameric carboxyltransferase core. We define the structural basis of substrate selectivity within the CT core: AccD5 selectively binds the short-chain substrate C3-CoA, whereas AccD4 accommodates the long-chain substrate C16-CoA.
In addition, we resolve AccD5-centered assemblies that associate with biotin carboxylase modules yet lack AccD4, providing structural evidence that distinct carboxyltransferase cores can engage shared modules to generate alternative holoenzyme architectures. Together, these findings define LCC and AccD5-centered assemblies as elements of a combinatorial acyl-CoA carboxylase platform and establish the structural principles governing assembly-specific function in mycobacteria.
Competing Interest Statement
The authors have declared no competing interest.
Footnotes
Version update statement In the course of preparing cryo-EM validation reports for journal submission, we re-evaluated the corresponding reconstructions and map assignments. This analysis revealed that a conformational state previously interpreted as an open form of LCC instead corresponds to an AccD5-centered assembly (ACCase 5). The manuscript has been revised accordingly to correct the structural assignment and refine the mechanistic interpretation. The updated version clarifies the distinction between the AccD4/AccD5 heterohexamer (LCC) and the AccD5 homohexamer (ACCase 5).
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