Biotin carboxyl carrier protein

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Biotin Carboxyl Carrier Protein BCCP.png
Biotin Carboxyl Carrier Protein

Biotin carboxyl carrier protein (BCCP) refers to proteins containing a biotin attachment domain that carry biotin and carboxybiotin throughout the ATP-dependent carboxylation by biotin-dependent carboxylases. The biotin carboxyl carrier protein is an Acetyl CoA subunit that allows for Acetyl CoA to be catalyzed and converted to malonyl-CoA. More specifically, BCCP catalyzes the carboxylation of the carrier protein to form an intermediate. Then the carboxyl group is transferred by the transcacrboxylase to form the malonyl-CoA. [1] This conversion is an essential step in the biosynthesis of fatty acids. In the case of E. coli Acetyl-CoA carboxylase, the BCCP is a separate protein known as accB ( P0ABD8 ). On the other hand, in Haloferax mediterranei , propionyl-CoA carboxylase, the BCCP pccA ( I3R7G3 ) is fused with biotin carboxylase.

Contents

The biosynthesis of fatty acids in plants, such as triacylglycerol, is vital to the plant's overall health because it allows for accumulation of seed oil. The biosynthesis that is catalyzed by BCCP usually takes place in the chloroplast of plant cells. The biosynthesis performed by the BCCP protein allows for the transfer of CO2 within active sites of the cell. [2]

The biotin carboxyl carrier protein carries approximately 1 mol of biotin per 22,000 g of protein. [3]

There is not much research on BCCPs at the moment. However, a recent studyon plant genomics found that Brassica BCCPs might play a key role in abiotic and biotic stress responses. [4] Meaning that these proteins may be relaying messages to the rest of the plant body after it has been exposed to extreme conditions that disrupt the plant's homeostasis.

Synthesis of Malonyl-CoA

Synthesis Mechanism of Malonyl-CoA
Synthesis of Malonyl-CoA.jpg

The synthesis of Malonyl-CoA consists of two half reactions. The first being the carboxylation of biotin with bicarbonate and the second being the transfer of the CO2 group to acetyl-CoA from carboxybiotin to allow for the formation of malonyl-CoA. Two different protein subassemblies, along with BCCP, are required for this two step reaction to be successful: biotin carboxylase (BC) and carboxyltransferase (CT). BCCP contains the biotin cofactor which is covalently bound to a lysine residue. [5]

In fungi, mammals, and plant cytosols, all three of these components (BCCP, BC, and CT) exist on one polypeptide chain. However, most studies of this protein have been conducted on the E. coli form of the enzyme, where all three components exist as three separate complexes rather than being united on one polypeptide chain.

Structure

E. coli BCCP-87 and the 1.3S subunit of P. shermanii TC
3-s2.0-B9780123786302000050-gr3.jpg
Three-dimensional structures of two biotin domains. The structures of the biotin domains from the biotin carboxyl carrier protein (BCCP) of (left) Escherichia coli acetyl CoA carboxylase and (right) the 1.3S subunit of Propionibacterium freudenreichii subsp. shermanii transcarboxylase (TC).

The first report of the BCCP structure was made by biochemists F. K. Athappilly and W. A. Hendrickson in 1995. [6] It can be thought of as a long β-hairpin structure, with four pairs of antiparallel β-strands that wrap around a central hydrophobic core. The biotinylation motif Met-Lys-Met is located at the tip of the β-hairpin structure. Rotations around the CαCβ bond of this Lys residue contribute to the swinging-arm model. The connection to the rest of the enzyme at the N-terminus of BCCP core is located at the opposite end of the structure from the biotin moiety. Rotations around this region contribute to the swinging-domain model, and the N1′ atom of biotin is ~ 40 Å from this pivot point. This gives a range of ~ 80 Å for the swinging-domain model, and the BC–CT active site distances observed so far are between 40 and 80 Å. [7] In addition, the linker before the BCCP core in the holoenzyme could also be flexible, which would give further reach for the biotin N1′ atom. [8]

The structures of biotin-accepting domains from E. coli BCCP-87 and the 1.3S subunit of P. shermanii TC were determined by both X-ray crystallography and nuclear magnetic resonance studies. (Athappilly and Hendrickson, 1995; Roberts et al., 1999; Reddy et al., 1998). [9] These produced essentially the same structures that are structurally related to the lipoyl domains of 2-oxo acid dehydrogenase multienzyme complexes (Brocklehurst and Perham, 1993; Dardel et al., 1993), which similarly undergo an analogous post-translational modification. These domains form a flattened β-barrel structure comprising two four-stranded β-sheets with the N- and C-terminal residues close together at one end of the structure. At the other end of the molecule, the biotinyl- or lipoyl-accepting lysine resides on a highly exposed, tight hairpin loop between β4 and β5 strands. The structure of the domain is stabilized by a core of hydrophobic residues, which are important structural determinants. Conserved glycine residues occupy β-turns linking the β-strands. [10]

The structure of the Biotin-accepting domain consists of BCCP-87 which contains a seven-amino-acid insertion common to certain prokaryotic acetyl-CoA carboxylases but not present in other biotindomains (Chapman-Smith and Cronan, 1999). This region of the peptide adopts a thumb structure between the β2 and β3 strands and, interestingly, forms direct contacts with the biotin moiety in both the crystal and solution structures (Athappilly and Hendrickson, 1995; Roberts et al., 1999). It has been proposed that this thumb may function as a mobile lid for either, or possibly both, the biotin carboxylase or carboxyl- transferase active sites in the biotin-dependent enzyme (Cronan, 2001). The function of this lid could aid to prevent solvation of the active sites, thereby aiding in the transfer of CO2 from carboxybiotin to acetyl CoA. Secondly, the thumb is required for dimerization of BCCP, necessary for the formation of the active acetyl CoA carboxylase complex (Cronan, 2001). In conclusion, the thumb functions to inhibit the aberrant lipoylation of the target lysine by lipoyl protein ligase (Reche and Perham, 1999). Removal of the thumb by mutagenesis rendered BCCP-87 a favorable substrate for lipoylation but abolished biotinylation (Reche and Perham, 1999). The thumb structure, however, is not a highly conserved feature amongst all biotin domains. Many biotin-dependent enzymes do not contain this insertion, including all five mammalian enzymes. However, it appears the interactions between biotin and protein might be a conserved feature and important for catalysis as similar contacts have been observed in the "thumbless" domains from P. shermanii transcarboxylase (Jank et al., 2002) and the biotinyl/lipoyl attachment protein of B. subtilis (Cui et al., 2006). The significance of this requires further investigation but it is possible that the mechanism employed by the biotin enzymes may involve noncovalent interactions between the protein and the prosthetic group.

Related Research Articles

<span class="mw-page-title-main">Acetyl-CoA</span> Chemical compound

Acetyl-CoA is a molecule that participates in many biochemical reactions in protein, carbohydrate and lipid metabolism. Its main function is to deliver the acetyl group to the citric acid cycle to be oxidized for energy production.

<span class="mw-page-title-main">Pyruvate carboxylase</span> Enzyme

Pyruvate carboxylase (PC) encoded by the gene PC is an enzyme of the ligase class that catalyzes the physiologically irreversible carboxylation of pyruvate to form oxaloacetate (OAA).

<span class="mw-page-title-main">Acetyl-CoA carboxylase</span> Enzyme that regulates the metabolism of fatty acids

Acetyl-CoA carboxylase (ACC) is a biotin-dependent enzyme that catalyzes the irreversible carboxylation of acetyl-CoA to produce malonyl-CoA through its two catalytic activities, biotin carboxylase (BC) and carboxyltransferase (CT). ACC is a multi-subunit enzyme in most prokaryotes and in the chloroplasts of most plants and algae, whereas it is a large, multi-domain enzyme in the cytoplasm of most eukaryotes. The most important function of ACC is to provide the malonyl-CoA substrate for the biosynthesis of fatty acids. The activity of ACC can be controlled at the transcriptional level as well as by small molecule modulators and covalent modification. The human genome contains the genes for two different ACCs—ACACA and ACACB.

<span class="mw-page-title-main">Oxaloacetate decarboxylase</span> Enzyme

Oxaloacetate decarboxylase is a carboxy-lyase involved in the conversion of oxaloacetate into pyruvate.

Propionyl-CoA is a coenzyme A derivative of propionic acid. It is composed of a 24 total carbon chain and its production and metabolic fate depend on which organism it is present in. Several different pathways can lead to its production, such as through the catabolism of specific amino acids or the oxidation of odd-chain fatty acids. It later can be broken down by propionyl-CoA carboxylase or through the methylcitrate cycle. In different organisms, however, propionyl-CoA can be sequestered into controlled regions, to alleviate its potential toxicity through accumulation. Genetic deficiencies regarding the production and breakdown of propionyl-CoA also have great clinical and human significance.

<span class="mw-page-title-main">Propionyl-CoA carboxylase</span>

Propionyl-CoA carboxylase (EC 6.4.1.3, PCC) catalyses the carboxylation reaction of propionyl-CoA in the mitochondrial matrix. PCC has been classified both as a ligase and a lyase. The enzyme is biotin-dependent. The product of the reaction is (S)-methylmalonyl CoA.

Methylcrotonyl CoA carboxylase is a biotin-requiring enzyme located in the mitochondria. MCC uses bicarbonate as a carboxyl group source to catalyze the carboxylation of a carbon adjacent to a carbonyl group performing the fourth step in processing leucine, an essential amino acid.

A tether is a form of cell surface protrusion, separated from the cytoskeleton after the application of low pulling forces to the cell surface membrane. They are thin, viscoelastic tubes which can be observed in vivo due to shear flow caused by molecular bonds between blood cells and vessel walls, for example.

Carboxylation is a chemical reaction in which a carboxylic acid is produced by treating a substrate with carbon dioxide. The opposite reaction is decarboxylation. In chemistry, the term carbonation is sometimes used synonymously with carboxylation, especially when applied to the reaction of carbanionic reagents with CO2. More generally, carbonation usually describes the production of carbonates.

In biochemistry, fatty acid synthesis is the creation of fatty acids from acetyl-CoA and NADPH through the action of enzymes called fatty acid synthases. This process takes place in the cytoplasm of the cell. Most of the acetyl-CoA which is converted into fatty acids is derived from carbohydrates via the glycolytic pathway. The glycolytic pathway also provides the glycerol with which three fatty acids can combine to form triglycerides, the final product of the lipogenic process. When only two fatty acids combine with glycerol and the third alcohol group is phosphorylated with a group such as phosphatidylcholine, a phospholipid is formed. Phospholipids form the bulk of the lipid bilayers that make up cell membranes and surrounds the organelles within the cells. In addition to cytosolic fatty acid synthesis, there is also mitochondrial fatty acid synthesis (mtFASII), in which malonyl-CoA is formed from malonic acid with the help of malonyl-CoA synthetase (ACSF3), which then becomes the final product octanoyl-ACP (C8) via further intermediate steps.

<span class="mw-page-title-main">Beta-ketoacyl-ACP synthase</span> Enzyme

In molecular biology, Beta-ketoacyl-ACP synthase EC 2.3.1.41, is an enzyme involved in fatty acid synthesis. It typically uses malonyl-CoA as a carbon source to elongate ACP-bound acyl species, resulting in the formation of ACP-bound β-ketoacyl species such as acetoacetyl-ACP.

<span class="mw-page-title-main">Biotin carboxylase</span> Class of enzymes

In enzymology, a biotin carboxylase (EC 6.3.4.14) is an enzyme that catalyzes the chemical reaction

In enzymology, a [acyl-carrier-protein] S-acetyltransferase is an enzyme that catalyzes the reversible chemical reaction

In enzymology, a [acyl-carrier-protein] S-malonyltransferase is an enzyme that catalyzes the chemical reaction

In enzymology, a lipoyl(octanoyl) transferase (EC 2.3.1.181) is an enzyme that catalyzes the chemical reaction

<span class="mw-page-title-main">Committed step</span> Step in enzymatic chemical reactions

In enzymology, the committed step is an effectively irreversible enzymatic reaction that occurs at a branch point during the biosynthesis of some molecules. As the name implies, after this step, the molecules are "committed" to the pathway and will ultimately end up in the pathway's final product. The first committed step should not be confused with the rate-limiting step, which is the step with the highest flux control coefficient. It is rare that the first committed step is in fact the rate-determining step.

<span class="mw-page-title-main">Cofactor transferase family</span>

In molecular biology, the Cofactor transferase family is a family of protein domains that includes biotin protein ligases, lipoate-protein ligases A, octanoyl-(acyl carrier protein):protein N-octanoyltransferases, and lipoyl-protein:protein N-lipoyltransferases. The metabolism of the cofactors Biotin and lipoic acid share this family. They also share the target modification domain, and the sulfur insertion enzyme.

Malonyl-S-ACP:biotin-protein carboxyltransferase is an enzyme with systematic name malonyl-(acyl-carrier protein):biotinyl-(protein) carboxytransferase. This enzyme catalyses the following chemical reaction

<span class="mw-page-title-main">Ketoacyl synthase</span> Catalyst for a key step in fatty acid synthesis

Ketoacyl synthases (KSs) catalyze the condensation reaction of acyl-CoA or acyl-acyl ACP with malonyl-CoA to form 3-ketoacyl-CoA or with malonyl-ACP to form 3-ketoacyl-ACP. This reaction is a key step in the fatty acid synthesis cycle, as the resulting acyl chain is two carbon atoms longer than before. KSs exist as individual enzymes, as they do in type II fatty acid synthesis and type II polyketide synthesis, or as domains in large multidomain enzymes, such as type I fatty acid synthases (FASs) and polyketide synthases (PKSs). KSs are divided into five families: KS1, KS2, KS3, KS4, and KS5.

Andrimid is an antibiotic natural product that is produced by the marine bacterium Vibrio coralliilyticus. Andrimid is an inhibitor of fatty acid biosynthesis by blocking the carboxyl transfer reaction of acetyl-CoA carboxylase (ACC).

References

  1. ↑ "UniProt". www.uniprot.org. Retrieved 2023-04-26.
  2. ↑ "InterPro". www.ebi.ac.uk. Retrieved 2023-04-26.
  3. ↑ Fall, R. Ray; Nervi, A. M.; Alberts, Alfred W.; Vagelos, P. Roy (July 1971). "Acetyl CoA Carboxylase: Isolation and Characterization of Native Biotin Carboxyl Carrier Protein". Proceedings of the National Academy of Sciences. 68 (7): 1512–1515. Bibcode:1971PNAS...68.1512F. doi: 10.1073/pnas.68.7.1512 . ISSN   0027-8424. PMC   389229 . PMID   4934522.
  4. ↑ Megha, Swati; Wang, Zhengping; Kav, Nat N. V.; Rahman, Habibur (2022-10-17). "Genome-wide identification of biotin carboxyl carrier subunits of acetyl-CoA carboxylase in Brassica and their role in stress tolerance in oilseed Brassica napus". BMC Genomics. 23 (1): 707. doi: 10.1186/s12864-022-08920-y . ISSN   1471-2164. PMC   9578262 . PMID   36253756.
  5. ↑ Choi-Rhee, Eunjoo (August 2003). "The Biotin Carboxylase-Biotin Carboxyl Carrier Protein Complex of Escherichia coli Acetyl-CoA Carboxylase". Journal of Biological Chemistry. 278 (33): 30806–30812. doi: 10.1074/jbc.M302507200 . PMID   12794081.
  6. ↑ Athappilly, F. K.; Hendrickson, W. A. (1995-12-15). "Structure of the biotinyl domain of acetyl-coenzyme A carboxylase determined by MAD phasing". Structure. 3 (12): 1407–1419. doi: 10.1016/s0969-2126(01)00277-5 . ISSN   0969-2126. PMID   8747466. S2CID   21461025.
  7. ↑ Rossen Donev, ed. (11 April 2023). Control of Cell Cycle & Cell Proliferation. Advances in Protein Chemistry and Structural Biology Vol. 135. Oxford [u.a.]: Academic Press. ISBN   978-0-443-15822-3.
  8. ↑ Tong, Liang (2017), Striking Diversity in Holoenzyme Architecture and Extensive Conformational Variability in Biotin-Dependent Carboxylases, Advances in Protein Chemistry and Structural Biology, vol. 109, Elsevier, pp. 161–194, doi:10.1016/bs.apcsb.2017.04.006, ISBN   978-0-12-811876-4
  9. ↑ Charles O. Rock, Suzanne Jackowski, John E. Cronan, Chapter 2 - Lipid metabolism in prokaryotes, Editor(s): Dennis E. Vance, Jean E. Vance, New Comprehensive Biochemistry, Elsevier, Volume 31, 1996, Pages 35-74, ISSN   0167-7306, ISBN   978-0-444-82359-5, doi : 10.1016/S0167-7306(08)60509-8.
  10. ↑ Lennarz, William J., and M. Daniel Lane. Encyclopedia of Biological Chemistry. Elsevier, 2013.
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