Striking Diversity in Holoenzyme Architecture and Extensive Conformational Variability in Biotin-Dependent Carboxylases

Tong, Liang

doi:10.1016/bs.apcsb.2017.04.006

Cited by 19 publications

(12 citation statements)

References 102 publications

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“…Carrier proteins and carrier domains are commonly used to shuttle covalently bound intermediates between remote active sites in large, multienzyme complexes, such as fatty acid synthases (FAS) 23 , polyketide synthases (PKS) 24 , non-ribosomal peptide synthetases (NRPS) 25 , pyruvate dehydrogenase 26 , and the broader family of biotin-dependent enzymes 27 . In all cases, the transfer of reaction intermediates between spatially distinct active sites requires long-range movements of the carrier domain during catalytic turnover.…”

Section: Discussionmentioning

confidence: 99%

Allosteric regulation alters carrier domain translocation in pyruvate carboxylase

et al. 2018

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Pyruvate carboxylase (PC) catalyzes the ATP-dependent carboxylation of pyruvate to oxaloacetate. The reaction occurs in two separate catalytic domains, coupled by the long-range translocation of a biotinylated carrier domain (BCCP). Here, we use a series of hybrid PC enzymes to examine multiple BCCP translocation pathways in PC. These studies reveal that the BCCP domain of PC adopts a wide range of translocation pathways during catalysis. Furthermore, the allosteric activator, acetyl CoA, promotes one specific intermolecular carrier domain translocation pathway. These results provide a basis for the ordered thermodynamic state and the enhanced carboxyl group transfer efficiency in the presence of acetyl CoA, and reveal that the allosteric effector regulates enzyme activity by altering carrier domain movement. Given the similarities with enzymes involved in the modular synthesis of natural products, the allosteric regulation of carrier domain movements in PC is likely to be broadly applicable to multiple important enzyme systems.

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Section: Discussionmentioning

confidence: 99%

Allosteric regulation alters carrier domain translocation in pyruvate carboxylase

et al. 2018

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“…Vitamin B7/8 is known under the name of biotin, which is a prosthetic group of five cellular carboxylases in humans (acetyl-CoA carboxylase 1 and 2 (ACC1, ACC2), propionyl-CoA carboxylase (PCC), 3-methylcrotonyl-CoA carboxylase (MCC), and pyruvate carboxylase (PC)), four of which are located at the outer membrane or in the matrix of mitochondria [ 103 ]. Interestingly, all these enzymes are involved in energy metabolism.…”

Section: Energy Metabolism and B Vitaminsmentioning

confidence: 99%

Metabolic Therapy of Heart Failure: Is There a Future for B Vitamins?

Piquereau

Boitard

Ventura‐Clapier

et al. 2021

IJMS

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Heart failure (HF) is a plague of the aging population in industrialized countries that continues to cause many deaths despite intensive research into more effective treatments. Although the therapeutic arsenal to face heart failure has been expanding, the relatively short life expectancy of HF patients is pushing towards novel therapeutic strategies. Heart failure is associated with drastic metabolic disorders, including severe myocardial mitochondrial dysfunction and systemic nutrient deprivation secondary to severe cardiac dysfunction. To date, no effective therapy has been developed to restore the cardiac energy metabolism of the failing myocardium, mainly due to the metabolic complexity and intertwining of the involved processes. Recent years have witnessed a growing scientific interest in natural molecules that play a pivotal role in energy metabolism with promising therapeutic effects against heart failure. Among these molecules, B vitamins are a class of water soluble vitamins that are directly involved in energy metabolism and are of particular interest since they are intimately linked to energy metabolism and HF patients are often B vitamin deficient. This review aims at assessing the value of B vitamin supplementation in the treatment of heart failure.

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“…Using bicarbonate as the carboxyl donor, a biotin carboxylase (BC) catalyzes MgATP-dependent carboxylation of a biotin cofactor, which is covalently linked to a lysine residue within the highly conserved sequence motif (E-X-M-K-M) of a biotin carboxyl carrier protein (BCCP) ( 9 ). Subsequently, a carboxyltransferase (CT) facilitates the transfer of the carboxylate group from carboxylbiotin to Ac-CoA, resulting in the formation of M-CoA and regeneration of biotin-BCCP ( 10 – 12 ). Specifically, the BCCP biotinylation is catalyzed by biotinyl protein ligase [BPL, such as E. coli biotin inducible repressor (BirA) and mammal holocarboxylase synthase (HCS)] in an ATP-dependent manner ( 13 – 15 ).…”

Section: Introductionmentioning

confidence: 99%

Chloroflexus aurantiacus acetyl-CoA carboxylase evolves fused biotin carboxylase and biotin carboxyl carrier protein to complete carboxylation activity

Shen,

Wu,

Wang

et al. 2024

mBio

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Acetyl-CoA carboxylases (ACCs) convert acetyl-CoA to malonyl-CoA, a key step in fatty acid biosynthesis and autotrophic carbon fixation pathways. Three functionally distinct components, biotin carboxylase (BC), biotin carboxyl carrier protein (BCCP), and carboxyltransferase (CT), are either separated or partially fused in different combinations, forming heteromeric ACCs. However, an ACC with fused BC-BCCP and separate CT has not been identified, leaving its catalytic mechanism unclear. Here, we identify two BC isoforms (BC1 and BC2) from Chloroflexus aurantiacus , a filamentous anoxygenic phototroph that employs 3-hydroxypropionate (3-HP) bi-cycle rather than Calvin cycle for autotrophic carbon fixation. We reveal that BC1 possesses fused BC and BCCP domains, where BCCP could be biotinylated by E. coli or C. aurantiacus BirA on Lys553 residue. Crystal structures of BC1 and BC2 at 3.2 Å and 3.0 Å resolutions, respectively, further reveal a tetramer of two BC1-BC homodimers, and a BC2 homodimer, all exhibiting similar BC architectures. The two BC1-BC homodimers are connected by an eight-stranded β-barrel of the partially resolved BCCP domain. Disruption of β-barrel results in dissociation of the tetramer into dimers in solution and decreased biotin carboxylase activity. Biotinylation of the BCCP domain further promotes BC1 and CTβ-CTα interactions to form an enzymatically active ACC, which converts acetyl-CoA to malonyl-CoA in vitro and produces 3-HP via co-expression with a recombinant malonyl-CoA reductase in E. coli cells. This study revealed a heteromeric ACC that evolves fused BC-BCCP but separate CTα and CTβ to complete ACC activity. IMPORTANCE Acetyl-CoA carboxylase (ACC) catalyzes the rate-limiting step in fatty acid biosynthesis and autotrophic carbon fixation pathways across a wide range of organisms, making them attractive targets for drug discovery against various infections and diseases. Although structural studies on homomeric ACCs, which consist of a single protein with three subunits, have revealed the “swing domain model” where the biotin carboxyl carrier protein (BCCP) domain translocates between biotin carboxylase (BC) and carboxyltransferase (CT) active sites to facilitate the reaction, our understanding of the subunit composition and catalytic mechanism in heteromeric ACCs remains limited. Here, we identify a novel ACC from an ancient anoxygenic photosynthetic bacterium Chloroflexus aurantiacus , it evolves fused BC and BCCP domain, but separate CT components to form an enzymatically active ACC, which converts acetyl-CoA to malonyl-CoA in vitro and produces 3-hydroxypropionate (3-HP) via co-expression with recombinant malonyl-CoA reductase in E. coli cells. These findings expand the diversity and molecular evolution of heteromeric ACCs and provide a structural basis for potential applications in 3-HP biosynthesis.

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Striking Diversity in Holoenzyme Architecture and Extensive Conformational Variability in Biotin-Dependent Carboxylases

Cited by 19 publications

References 102 publications

Allosteric regulation alters carrier domain translocation in pyruvate carboxylase

Allosteric regulation alters carrier domain translocation in pyruvate carboxylase

Metabolic Therapy of Heart Failure: Is There a Future for B Vitamins?

Chloroflexus aurantiacus acetyl-CoA carboxylase evolves fused biotin carboxylase and biotin carboxyl carrier protein to complete carboxylation activity

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