World Library  
Flag as Inappropriate
Email this Article

Propionyl-CoA carboxylase

Article Id: WHEBN0008430729
Reproduction Date:

Title: Propionyl-CoA carboxylase  
Author: World Heritage Encyclopedia
Language: English
Subject: Methylmalonyl CoA epimerase, Methylcrotonyl-CoA carboxylase, Beta oxidation, Glutathione synthetase, Chromosome 13 (human)
Collection: Ec 6.4.1
Publisher: World Heritage Encyclopedia

Propionyl-CoA carboxylase

Propionyl-CoA carboxylase
EC number
CAS number 9023-94-3
IntEnz IntEnz view
ExPASy NiceZyme view
MetaCyc metabolic pathway
PRIAM profile
PDB structures RCSB PDB PDBe PDBsum
Gene Ontology AmiGO / EGO
Methylmalonyl-CoA decarboxylase
EC number
CAS number 37289-44-4
IntEnz IntEnz view
ExPASy NiceZyme view
MetaCyc metabolic pathway
PRIAM profile
PDB structures RCSB PDB PDBe PDBsum
Gene Ontology AmiGO / EGO

Propionyl-CoA carboxylase catalyses the carboxylation reaction of propionyl CoA in the mitochondrial matrix. The enzyme is biotin-dependent. The product of the reaction is (S)-methylmalonyl CoA. Propionyl CoA is the end product of metabolism of odd-chain fatty acids, and is also a metabolite of most methyl-branched fatty acids. It is also the main metabolite of valine, and together with acetyl-CoA, is a metabolite of isoleucine, as well as a methionine metabolite. Propionyl-CoA is thus of great importance as a glucose precursor. (S)-Methylmalonyl-CoA is not directly utilizable by animals; it is acted on by a racemase to give (R)-methylmalonyl-CoA. The latter is converted by methylmalonyl-CoA mutase (one of a very few Vitamin B12-dependent enzymes) to give succinyl-CoA. The latter is converted to oxaloacetate and then malate in the Krebs cycle. Export of malate into the cytosol leads to formation of oxaloacetate, phosphoenol pyruvate, and other gluconeogenic intermediates.

ATP + propionyl-CoA + HCO3- <=> ADP + phosphate + (S)-methylmalonyl-CoA

It has been classified both as a ligase[1] and a lyase.[2]


  • Enzyme Structure 1
  • Enzyme Mechanism 2
  • Isozymes 3
  • Pathology 4
  • Regulation 5
    • Of Propionyl-CoA Carboxylase 5.1
    • By Propionyl-CoA Carboxylase 5.2
  • See also 6
  • References 7
  • External links 8

Enzyme Structure

Propionyl-CoA Carboxylase (PCC) is a 750 kDa alpha(6)-beta(6)-dodecamer. (Only approximately 540 kDa is native enzyme. [3] ) The alpha subunits are arranged as monomers, decorating the central beta-6 hexameric core. Said core is oriented as a short cylinder with a hole along its axis.

The alpha subunit of PCC contains the biotin carboxylase (BC) and biotin carboxyl carrier protein (BCCP) domains. A domain known as the BT domain is also located on the alpha subunit and is essential for interactions with the beta subunit. The 8-stranded anti-parallel beta barrel fold of this domain is particularly interesting. The beta subunit contains the carboxyltransferase (CT) activity.[4]

Figure 1.(a). Schematic drawing of the structure of the RpPCCα-RdPCCβ chimera, viewed down the three-fold symmetry axis. Domains in the α and β subunits in the top half of the structure are given different colors, and those in the first α and β subunits are labeled. The α and β subunits in the bottom half are colored in magenta and green, respectively. The red arrow indicates the viewing direction of panel b. (b). Structure of the RpPCCα-RdPCCβ chimera, viewed down the two-fold symmetry axis. The red rectangle indicates the region shown in detail in Fig. 2a. (c). Cryo-EM reconstruction of HsPCC at 15 Å resolution, viewed in the same orientation as panel a. The atomic model of the chimera was fit into the cryo-EM envelope. (d). The cryo-EM reconstruction viewed in the same orientation as panel b. The arrows indicate a change in the BCCP position that is needed to fit the cryo-EM map. All the structure figures were produced with PyMOL (, and the cryo-EM figures were produced with Chimera.[5] This provides clear evidence of crucial dimeric interaction between alpha and beta subunits.

The BC and CT sites are approximately 55 Å apart, indicative of the entire BCCP domain translocating during catalysis of the carboxylation of propionyl-CoA. [5] This provides clear evidence of crucial dimeric interaction between alpha and beta subunits.

Figure 2.(a). Schematic drawing of the relative positioning of the BC and CT active sites in the holoenzyme. One α subunit and a β2 dimer (β1 from one layer and β4 from the other layer) are shown, and the viewing direction is the same as Fig. 1b. The two active sites are indicated with the stars, separated by 55 Å distance. The bound positions of ADP in complex with E. coli BC 18 and that of CoA in complex with the 12S subunit of transcarboxylase 21 are also shown. (b). Detailed interactions between BCCP-biotin and the C domain of a β subunit. Hydrogen-bonding interactions are indicated with the dashed lines in red. The N1′ atom of biotin is labeled as 1′, hydrogen-bonded to the main-chain carbonyl of Phe397. (c). Molecular surface of the CT active site, showing a deep canyon where both substrates are bound. (d). Schematic drawing of the CT active site.[5]

The biotin-binding pocket of PCC is hydrophobic and highly conserved. Biotin and propionyl-CoA bind perpendicular to each other in the oxyanion hole-containing active site. The native enzyme to biotin ratio has been determined to be one mole native enzyme to 4 moles biotin. [3] The N1 of biotin is thought to be the active site base.[4]

Site-directed mutagenesis at D422 shows a change in the substrate specificity of the propionyl-CoA binding site, thus indicating this residue’s importance in PCC’s catalytic activity. [6] In 1979, inhibition by phenylglyoxal determined that a phosphate group from either propionyl-CoA or ATP reacts with an essential arginine residue in the active site during catalysis.[7] Later (2004), it was suggested that Arginine-338 serves to orient the carboxyphosphate intermediate for optimal carboxylation of biotin. [8]

The KM values for ATP, propionyl-CoA, and bicarbonate has been determined to be 0.08 mM, 0.29 mM, and 3.0 mM, respectively. The isoelectric point falls at pH 5.5. PCC’s structural integrity is conserved over the temperature range of -50 to 37 degrees Celsius and the pH range of 6.2 to 8.8. Optimum pH was shown to be between 7.2 and 8.8 without biotin bound.[3] With biotin, optimum pH is 8.0-8.5.[9]

Enzyme Mechanism

The normal catalytic reaction mechanism involves a carbanion intermediate and does not proceed through a concerted process.[10] Figure 3 shows a probable pathway.

Figure 3. Probable PCC Mechanism

The reaction has been shown to be slightly reversible at low propionyl-CoA flux.[11]


Humans express the following two propionyl-CoA carboxylase isozymes:
propionyl Coenzyme A carboxylase, alpha polypeptide
Symbol PCCA
Entrez 5095
HUGO 8653
OMIM 232000
RefSeq NM_000282
UniProt P05165
Other data
EC number
Locus Chr. 13 q32
propionyl Coenzyme A carboxylase, beta polypeptide
Symbol PCCB
Entrez 5096
HUGO 8654
OMIM 232050
RefSeq NM_000532
UniProt P05166
Other data
EC number
Locus Chr. 3 q21-q22


A deficiency is associated with propionic acidemia.[12][13][14]

PCC activity is the most sensitive indicator of biotin status tested to date. In future pregnancy studies, the use of lymphocyte PCC activity data should prove valuable in assessment of biotin status.[15]


Of Propionyl-CoA Carboxylase

a. Carbamazepine (antiepileptic drug): significantly lowers enzyme levels in the liver[16]

b. E. coli chaperonin proteins groES and groEL: essential for folding and assembly of human PCC heteromeric subunits[17]

c. Bicarbonate: negative cooperativity[8]

d. Mg2+ and MgATP2-: allosteric activation[18]

By Propionyl-CoA Carboxylase

a. 6-Deoxyerythronolide B: decrease in PCC levels lead to increased production [19]

b. Glucokinase in pancreatic beta cells: precursor of beta-PCC shown to decrease KM and increase Vmax; activation [20]

See also


  1. ^ EC
  2. ^ EC
  3. ^ a b c Kalousek F, Darigo MD, Rosenberg LE (1980). "Isolation and characterization of propionyl-CoA carboxylase from normal human liver. Evidence for a protomeric tetramer of nonidentical subunits". The Journal of biological chemistry 255 (1): 60–65.  
  4. ^ a b Diacovich L, Mitchell DL, Pham H, Gago G, Melgar MM, Khosla C, Gramajo H, Tsai SC (2004). "Crystal Structure of theβ-Subunit of Acyl-CoA Carboxylase:  Structure-Based Engineering of Substrate Specificity†,‡". Biochemistry 43 (44): 14027–14036.  
  5. ^ a b c Huang CS, Sadre-Bazzaz K, Shen Y, Deng B, Zhou ZH, Tong L (2010). "Crystal structure of the α6β6 holoenzyme of propionyl-coenzyme a carboxylase". Nature 466 (7309): 1001–1005.  
  6. ^ Arabolaza A, Shillito ME, Lin TW, Diacovich L, Melgar M, Pham H, Amick D, Gramajo H, Tsai SC (2010). "Crystal Structures and Mutational Analyses of Acyl-CoA Carboxylase β Subunit ofStreptomyces coelicolor". Biochemistry 49 (34): 7367–7376.  
  7. ^ Wolf B, Kalousek F, Rosenberg LE (1979). "Essential arginine residues in the active sites of propionyl CoA carboxylase and beta-methylcrotonyl CoA carboxylase". Enzyme 24 (5): 302–306.  
  8. ^ a b Sloane V, Waldrop GL (2004). "Kinetic characterization of mutations found in propionic acidemia and methylcrotonylglycinuria: evidence for cooperativity in biotin carboxylase.". Journal of Biological Chemistry 279 (16): 15772–15778.  
  9. ^ Hsia YE, Scully KJ, Rosenberg LE (1979). "Human propionyl CoA carboxylase: Some properties of the partially purified enzyme in fibroblasts from controls and patients with propionic acidemia". Pediatric research 13 (6): 746–751.  
  10. ^ Stubbe J, Fish S, Abeles RH (1980). "Are carboxylations involving biotin concerted or nonconcerted?". The Journal of biological chemistry 255 (1): 236–242.  
  11. ^ Reszko AE, Kasumov T, Pierce BA, David F, Hoppel CL, Stanley WC, Des Rosiers C, Brunengraber H (2003). "Assessing the Reversibility of the Anaplerotic Reactions of the Propionyl-CoA Pathway in Heart and Liver". Journal of Biological Chemistry 278 (37): 34959–34965.  
  12. ^ Ugarte M, Pérez-Cerdá C, Rodríguez-Pombo P, Desviat LR, Pérez B, Richard E, Muro S, Campeau E, Ohura T, Gravel RA (1999). "Overview of mutations in thePCCA andPCCB genes causing propionic acidemia". Human Mutation 14 (4): 275–282.  
  13. ^ Desviat LR, Pérez B, Pérez-Cerdá C, Rodríguez-Pombo P, Clavero S, Ugarte M (2004). "Propionic acidemia: Mutation update and functional and structural effects of the variant alleles". Molecular Genetics and Metabolism 83 (1–2): 28–37.  
  14. ^ Deodato, F.; Boenzi, S.; Santorelli, F. M.; Dionisi-Vici, C. (2006). "Methylmalonic and propionic aciduria". American Journal of Medical Genetics Part C: Seminars in Medical Genetics 142C (2): 104–112.  
  15. ^ Stratton SL, Bogusiewicz A, Mock MM, Mock NI, Wells AM, Mock DM (2006). "Lymphocyte propionyl-CoA carboxylase and its activation by biotin are sensitive indicators of marginal biotin deficiency in humans". The American journal of clinical nutrition 84 (2): 384–388.  
  16. ^ Rathman SC, Eisenschenk S, McMahon RJ (2002). "The abundance and function of biotin-dependent enzymes are reduced in rats chronically administered carbamazepine". The Journal of nutrition 132 (11): 3405–3410.  
  17. ^ Kelson TL, Ohura T, Kraus JP; Ohura; Kraus (1996). "Chaperonin-mediated assembly of wild-type and mutant subunits of human propionyl-CoA carboxylase expressed in Escherichia coli". Human molecular genetics 5 (3): 331–337.  
  18. ^ McKeon C, Wolf B (1982). "Magnesium and magnesium adenosine triphosphate activation of human propionyl CoA carboxylase and beta-methylcrotonyl CoA carboxylase". Enzyme 28 (1): 76–81.  
  19. ^ Zhang H, Boghigian BA, Pfeifer BA (2010). "Investigating the role of native propionyl-CoA and methylmalonyl-CoA metabolism on heterologous polyketide production inEscherichia coli". Biotechnology and Bioengineering 105 (3): 567–573.  
  20. ^ Shiraishi A, Yamada Y, Tsuura Y, Fijimoto S, Tsukiyama K, Mukai E, Toyoda Y, Miwa I, Seino Y (2000). "A novel glucokinase regulator in pancreatic beta cells: precursor of propionyl-CoA carboxylase beta subunit interacts with glucokinase and augments its activity.". Journal of Biological Chemistry 276 (4): 2325–2328.  

External links

This article was sourced from Creative Commons Attribution-ShareAlike License; additional terms may apply. World Heritage Encyclopedia content is assembled from numerous content providers, Open Access Publishing, and in compliance with The Fair Access to Science and Technology Research Act (FASTR), Wikimedia Foundation, Inc., Public Library of Science, The Encyclopedia of Life, Open Book Publishers (OBP), PubMed, U.S. National Library of Medicine, National Center for Biotechnology Information, U.S. National Library of Medicine, National Institutes of Health (NIH), U.S. Department of Health & Human Services, and, which sources content from all federal, state, local, tribal, and territorial government publication portals (.gov, .mil, .edu). Funding for and content contributors is made possible from the U.S. Congress, E-Government Act of 2002.
Crowd sourced content that is contributed to World Heritage Encyclopedia is peer reviewed and edited by our editorial staff to ensure quality scholarly research articles.
By using this site, you agree to the Terms of Use and Privacy Policy. World Heritage Encyclopedia™ is a registered trademark of the World Public Library Association, a non-profit organization.

Copyright © World Library Foundation. All rights reserved. eBooks from Project Gutenberg are sponsored by the World Library Foundation,
a 501c(4) Member's Support Non-Profit Organization, and is NOT affiliated with any governmental agency or department.