carbon carbon ligases


Summary: Enzymes that catalyze the joining of two molecules by the formation of a carbon-carbon bond. These are the carboxylating enzymes and are mostly biotinyl-proteins. EC 6.4.

Top Publications

  1. Darin N, Andersen O, Wiklund L, Holmgren D, Holme E. 3-methylcrotonyl-CoA carboxylase deficiency and severe multiple sclerosis. Pediatr Neurol. 2007;36:132-4 pubmed
    ..Treatment with steroids had initially a good therapeutic effect on the relapses. The response to interferon beta-1a treatment was poor. On mitoxantrone treatment there was a considerable neurologic recovery. ..
  2. Darghouth D, Hallgren K, Shtofman R, Mrad A, Gharbi Y, Maherzi A, et al. Compound heterozygosity of novel missense mutations in the gamma-glutamyl-carboxylase gene causes hereditary combined vitamin K-dependent coagulation factor deficiency. Blood. 2006;108:1925-31 pubmed
    ..The implications for carboxylase mechanism are discussed. ..
  3. Lin T, Melgar M, Kurth D, Swamidass S, Purdon J, Tseng T, et al. Structure-based inhibitor design of AccD5, an essential acyl-CoA carboxylase carboxyltransferase domain of Mycobacterium tuberculosis. Proc Natl Acad Sci U S A. 2006;103:3072-7 pubmed
  4. Titapiwatanakun R, Rodriguez V, Middha S, Dukek B, Pruthi R. Novel splice site mutations in the gamma glutamyl carboxylase gene in a child with congenital combined deficiency of the vitamin K-dependent coagulation factors (VKCFD). Pediatr Blood Cancer. 2009;53:92-5 pubmed publisher
    ..Oral vitamin K supplementation resulted in partial resolution of proteins and complete resolution of bleeding. ..
  5. Rost S, Geisen C, Fregin A, Seifried E, Muller C, Oldenburg J. Founder mutation Arg485Pro led to recurrent compound heterozygous GGCX genotypes in two German patients with VKCFD type 1. Blood Coagul Fibrinolysis. 2006;17:503-7 pubmed
    ..The founder mutation explains that the only two compound heterozygous VKCFD type 1 patients known today originated from Germany. ..
  6. Murin R, Verleysdonk S, Rapp M, Hamprecht B. Immunocytochemical localization of 3-methylcrotonyl-CoA carboxylase in cultured ependymal, microglial and oligodendroglial cells. J Neurochem. 2006;97:1393-402 pubmed
    ..The ubiquitous expression of MCC in glial cells demonstrates the ability of the cells to engage in the catabolism of leucine transported into the brain, mainly for the generation of energy. ..
  7. Oh T, Daniel J, Kim H, Sirakova T, Kolattukudy P. Identification and characterization of Rv3281 as a novel subunit of a biotin-dependent acyl-CoA Carboxylase in Mycobacterium tuberculosis H37Rv. J Biol Chem. 2006;281:3899-908 pubmed
    ..The Rv3281 open reading frame is co-transcribed with Rv3280 in the mycobacterial cell, and the level of epsilon-protein was highest during the log phase and decreased during the stationary phase. ..
  8. Rodr guez E, Gramajo H. Genetic and biochemical characterization of the alpha and beta components of a propionyl-CoA carboxylase complex of Streptomyces coelicolor A3(2). Microbiology. 1999;145 ( Pt 11):3109-19 pubmed publisher
    ..The fact that accA2 mutants appear to be inviable suggests that this gene encodes a biotinylated protein that might be shared with other carboxyl transferases essential for the growth of S. coelicolor...
  9. Weston B, Monahan P. Familial deficiency of vitamin K-dependent clotting factors. Haemophilia. 2008;14:1209-13 pubmed publisher
    ..The results may also provide potential targets for molecular therapeutics and pharmacogenetics. ..

More Information


  1. Diacovich L, Mitchell D, Pham H, Gago G, Melgar M, Khosla C, et al. Crystal structure of the beta-subunit of acyl-CoA carboxylase: structure-based engineering of substrate specificity. Biochemistry. 2004;43:14027-36 pubmed publisher
    ..Our findings enable bioengineering of the acyl-CoA carboxylase (ACCase) substrate specificity to provide novel extender units for the combinatorial biosynthesis of polyketides...
  2. Diacovich L, Peirú S, Kurth D, Rodriguez E, Podestá F, Khosla C, et al. Kinetic and structural analysis of a new group of Acyl-CoA carboxylases found in Streptomyces coelicolor A3(2). J Biol Chem. 2002;277:31228-36 pubmed
    ..The epsilon subunit has been found genetically linked to several carboxyltransferases of different Streptomyces species; we propose that this subunit reflects a distinctive characteristic of a new group of acyl-CoA carboxylases. ..
  3. Rost S, Fregin A, Koch D, Compes M, Muller C, Oldenburg J. Compound heterozygous mutations in the gamma-glutamyl carboxylase gene cause combined deficiency of all vitamin K-dependent blood coagulation factors. Br J Haematol. 2004;126:546-9 pubmed
    ..Substitution of vitamin K could only partially normalize the levels of coagulation factors. It is suggested that the missense mutation affects either the propeptide binding site or the vitamin K binding site of GGCX. ..
  4. Rodriguez E, Banchio C, Diacovich L, Bibb M, Gramajo H. Role of an essential acyl coenzyme A carboxylase in the primary and secondary metabolism of Streptomyces coelicolor A3(2). Appl Environ Microbiol. 2001;67:4166-76 pubmed
  5. Oldenburg J, von Brederlow B, Fregin A, Rost S, Wolz W, Eberl W, et al. Congenital deficiency of vitamin K dependent coagulation factors in two families presents as a genetic defect of the vitamin K-epoxide-reductase-complex. Thromb Haemost. 2000;84:937-41 pubmed
    ..Further genetic analysis of such families will provide the basis for a more detailed understanding of the structure-function relation of the enzymes involved in vitamin K metabolism. ..
  6. Portevin D, de Sousa d Auria C, Montrozier H, Houssin C, Stella A, Lanéelle M, et al. The acyl-AMP ligase FadD32 and AccD4-containing acyl-CoA carboxylase are required for the synthesis of mycolic acids and essential for mycobacterial growth: identification of the carboxylation product and determination of the acyl-CoA carboxylase com. J Biol Chem. 2005;280:8862-74 pubmed
    ..smegmatis. Thus, in addition to Pks13, FadD32 and AccD4 are promising targets for the development of new antimicrobial drugs against pathogenic species of mycobacteria and related microorganisms. ..
  7. Wu S, Stafford D, Frazier L, Fu Y, High K, Chu K, et al. Genomic sequence and transcription start site for the human gamma-glutamyl carboxylase. Blood. 1997;89:4058-62 pubmed
    ..There are two major transcripts in all tissues examined. They are distinguished by the presence of an Alu sequence in the 3' nontranslated end of the longer species. Relative mRNA levels for 12 bovine tissues are presented. ..
  8. Baumgartner M, Dantas M, Suormala T, Almashanu S, Giunta C, Friebel D, et al. Isolated 3-methylcrotonyl-CoA carboxylase deficiency: evidence for an allele-specific dominant negative effect and responsiveness to biotin therapy. Am J Hum Genet. 2004;75:790-800 pubmed
    ..We show that MCCA-R385S, but not other MCCA missense alleles, reduces the MCC activity of cotransfected MCCA-wild-type allele. Our results suggest that MCCA-R385S is a dominant negative allele and is biotin responsive in vivo. ..
  9. Presnell S, Stafford D. The vitamin K-dependent carboxylase. Thromb Haemost. 2002;87:937-46 pubmed
  10. Wu S, Cheung W, Frazier D, Stafford D. Cloning and expression of the cDNA for human gamma-glutamyl carboxylase. Science. 1991;254:1634-6 pubmed
    ..3 percent identity with soybean seed lipoxygenase. Expression of the cloned cDNA resulted in an increase in carboxylase activity in microsomes of transfected cells compared to mock-transfected cells. ..
  11. Kinoshita H, Nakagawa K, Narusawa K, Goseki Sone M, Fukushi Irie M, Mizoi L, et al. A functional single nucleotide polymorphism in the vitamin-K-dependent gamma-glutamyl carboxylase gene (Arg325Gln) is associated with bone mineral density in elderly Japanese women. Bone. 2007;40:451-6 pubmed
    ..650+/-0.883, mean+/-SD) than those with 325-Arg/Gln or 325-Arg (0.133+/-0.650) (p=0.0383). This is the first report to demonstrate the different activities of GGCX between the common genotypes and their association with BMD. ..
  12. Mutucumarana V, Stafford D, Stanley T, Jin D, Solera J, Brenner B, et al. Expression and characterization of the naturally occurring mutation L394R in human gamma-glutamyl carboxylase. J Biol Chem. 2000;275:32572-7 pubmed
    ..To a lesser degree, the propeptide and KH(2) binding properties are altered in the L394R mutant. Compared with its wild-type counterpart, the L394R mutant shows an augmented activation of FLEEL carboxylation by the propeptide. ..
  13. Wajih N, Hutson S, Wallin R. Disulfide-dependent protein folding is linked to operation of the vitamin K cycle in the endoplasmic reticulum. A protein disulfide isomerase-VKORC1 redox enzyme complex appears to be responsible for vitamin K1 2,3-epoxide reduction. J Biol Chem. 2007;282:2626-35 pubmed
    ..We can conclude that the energy required for gamma-carboxylation of proteins is provided by dithiol-dependent oxidative protein folding in the ER and thus is linked to de novo protein synthesis. ..
  14. Rodriguez Melendez R. [Importance of biotin metabolism]. Rev Invest Clin. 2000;52:194-9 pubmed
    ..In humans, there are autosomal recessive disorders of biotin metabolism that result from the disruption of the activity of biotinidase or holo-carboxylase synthetase. ..
  15. Hansson K, Thamlitz A, Furie B, Furie B, Stenflo J. A single gamma-carboxyglutamic acid residue in a novel cysteine-rich secretory protein without propeptide. Biochemistry. 2006;45:12828-39 pubmed
    ..The results define a new class of Gla proteins and support the notion that gamma-carboxylation of glutamyl residues is phylogenetically older than blood coagulation and the vertebrate lineage. ..
  16. Helm R, Mock N, Simpson P, Mock D. Certain immune markers are not good indicators of mild to moderate biotin deficiency in rats. J Nutr. 2001;131:3231-6 pubmed
    ..We conclude that the immune markers examined are not promising candidates as indicators of mild to moderate deficiency in humans. ..
  17. Rai A, Udar N, Saad R, Fleisher M. A multiplex assay for detecting genetic variations in CYP2C9, VKORC1, and GGCX involved in warfarin metabolism. Clin Chem. 2009;55:823-6 pubmed publisher
    ..These data provide a proof-in-principle of multiplexed SNP analysis using rapid single-base extension and capillary electrophoresis, and warrant additional validation using a larger cohort of patient samples. ..
  18. Gilbert K, Rannels S. Glucocorticoid effects on vitamin K-dependent carboxylase activity and matrix Gla protein expression in rat lung. Am J Physiol Lung Cell Mol Physiol. 2003;285:L569-77 pubmed
    ..We propose that glucocorticoids are important regulators of vitamin K function in the developing and adult lung. ..
  19. Krossøy C, Lock E, Ørnsrud R. Vitamin K-dependent gamma-glutamylcarboxylase in Atlantic salmon (Salmo salar L.). Fish Physiol Biochem. 2010;36:627-635 pubmed publisher
    ..We propose the GGCX assay as a sensitive marker for vitamin K status, and confirm that menadione does not work as a cofactor for GGCX in Atlantic salmon liver. ..
  20. Azuma K, Inoue S. [Vitamin K function mediated by activation of steroid and xenobiotic receptor]. Clin Calcium. 2009;19:1770-8 pubmed publisher
    ..It has been also suggested that vitamin K could prevent or treat the hepatocellular carcinoma (HCC) in some clinical studies. SXR may also contribute to the vitamin K-dependent reduction of HCC. ..
  21. Bagautdinov B, Kuroishi C, Sugahara M, Kunishima N. Crystal structures of biotin protein ligase from Pyrococcus horikoshii OT3 and its complexes: structural basis of biotin activation. J Mol Biol. 2005;353:322-33 pubmed publisher
  22. Stadler S, Polanetz R, Maier E, Heidenreich S, Niederer B, Mayerhofer P, et al. Newborn screening for 3-methylcrotonyl-CoA carboxylase deficiency: population heterogeneity of MCCA and MCCB mutations and impact on risk assessment. Hum Mutat. 2006;27:748-59 pubmed
  23. Lamhonwah A, Barankiewicz T, Willard H, Mahuran D, Quan F, Gravel R. Isolation of cDNA clones coding for the alpha and beta chains of human propionyl-CoA carboxylase: chromosomal assignments and DNA polymorphisms associated with PCCA and PCCB genes. Proc Natl Acad Sci U S A. 1986;83:4864-8 pubmed
    ..Restriction fragment length polymorphisms were identified, at both PCCA and PCCB, that should prove useful to individual families at risk for propionic acidemia. ..
  24. Fu X, Wang X, Mernitz H, Wallin R, Shea M, Booth S. 9-Cis retinoic acid reduces 1alpha,25-dihydroxycholecalciferol-induced renal calcification by altering vitamin K-dependent gamma-carboxylation of matrix gamma-carboxyglutamic acid protein in A/J male mice. J Nutr. 2008;138:2337-41 pubmed publisher
    ..The mechanisms by which 9-cis RA and 1,25(OH)(2)D3 alter vitamin K concentrations warrant further investigation. ..
  25. Elpeleg O, Havkin S, Barash V, Jakobs C, Glick B, Shalev R. Familial hypotonia of childhood caused by isolated 3-methylcrotonyl-coenzyme A carboxylase deficiency. J Pediatr. 1992;121:407-10 pubmed
    ..We conclude that 3-methylcrotonyl-coenzyme A carboxylase deficiency should be added to the list of metabolic causes of familial hypotonia of childhood. ..
  26. Dirik E, Yis U, Paşaoğlu G, Chambaz C, Baumgartner M. Recurrent attacks of status epilepticus as predominant symptom in 3-methylcrotonyl-CoA carboxylase deficiency. Brain Dev. 2008;30:218-20 pubmed
    ..Deficiency of MCC was confirmed in cultured fibroblasts and mutation analysis revealed a novel mutation in MCCB, p.S39F. Attacks of status epilepticus as a predominant symptom have not been described before in isolated MCC deficiency. ..
  27. Bandyopadhyay P, Colledge C, Walker C, Zhou L, Hillyard D, Olivera B. Conantokin-G precursor and its role in gamma-carboxylation by a vitamin K-dependent carboxylase from a Conus snail. J Biol Chem. 1998;273:5447-50 pubmed
    ..However, the role of propeptide in enhancing the efficiency of carboxylation is maintained. ..
  28. Oldenburg J, Marinova M, Müller Reible C, Watzka M. The vitamin K cycle. Vitam Horm. 2008;78:35-62 pubmed publisher
  29. Lal S, Jada S, Xiang X, Lim W, Lee E, Chowbay B. Pharmacogenetics of target genes across the warfarin pharmacological pathway. Clin Pharmacokinet. 2006;45:1189-200 pubmed
    ..Understanding the causal relationship of these polygenic influences on warfarin dose requirements in patients of different ethnicity may be vital in reducing inter-patient variability and optimising anticoagulant therapy. ..
  30. Dunn M, Araíza G, Mora J. Biochemical characterization of a Rhizobium etli monovalent cation-stimulated acyl-coenzyme A carboxylase with a high substrate specificity constant for propionyl-coenzyme A. Microbiology. 2004;150:399-406 pubmed
    ..The strong kinetic preference of the enzyme for propionyl-CoA is consistent with its participation in an anaplerotic pathway utilizing this substrate. ..
  31. Klundt T, Bocola M, Lütge M, Beuerle T, Liu B, Beerhues L. A single amino acid substitution converts benzophenone synthase into phenylpyrone synthase. J Biol Chem. 2009;284:30957-64 pubmed publisher
    ..PPS is a promising biotechnological tool for manipulating benzoate-primed biosynthetic pathways to produce novel compounds. ..
  32. Zhu A, Sun H, Raymond R, Furie B, Furie B, Bronstein M, et al. Fatal hemorrhage in mice lacking gamma-glutamyl carboxylase. Blood. 2007;109:5270-5 pubmed
  33. Koeberl D, Millington D, Smith W, Weavil S, Muenzer J, McCandless S, et al. Evaluation of 3-methylcrotonyl-CoA carboxylase deficiency detected by tandem mass spectrometry newborn screening. J Inherit Metab Dis. 2003;26:25-35 pubmed
    ..Long-term follow-up is needed to determine the outcome of presymptomatically diagnosed patients with 3-MCC deficiency by MS/MS newborn screening. ..
  34. Baumgartner M. Molecular mechanism of dominant expression in 3-methylcrotonyl-CoA carboxylase deficiency. J Inherit Metab Dis. 2005;28:301-9 pubmed
    ..Evidence is presented that MCCA-R385S is a dominant negative allele leading to biochemical abnormalities and clinical symptoms in heterozygous individuals and that it is responsive to pharmacological doses of biotin in vivo. ..
  35. Baykal T, Gokcay G, Ince Z, Dantas M, Fowler B, Baumgartner M, et al. Consanguineous 3-methylcrotonyl-CoA carboxylase deficiency: early-onset necrotizing encephalopathy with lethal outcome. J Inherit Metab Dis. 2005;28:229-33 pubmed
    ..Mutation analysis revealed a homozygous mutation in the splice acceptor site of intron 15 in the MCC beta-subunit. Early-onset severe necrotizing encephalopathy should be included in the differential diagnosis of isolated MCC deficiency...
  36. Song J, Wurtele E, Nikolau B. Molecular cloning and characterization of the cDNA coding for the biotin-containing subunit of 3-methylcrotonoyl-CoA carboxylase: identification of the biotin carboxylase and biotin-carrier domains. Proc Natl Acad Sci U S A. 1994;91:5779-83 pubmed
    ..These domains are arranged serially on the polypeptide, with the biotin carboxylase domain at the amino terminus and the biotin-carboxyl carrier domain at the carboxyl terminus...
  37. Tie J, Mutucumarana V, Straight D, Carrick K, Pope R, Stafford D. Determination of disulfide bond assignment of human vitamin K-dependent gamma-glutamyl carboxylase by matrix-assisted laser desorption/ionization time-of-flight mass spectrometry. J Biol Chem. 2003;278:45468-75 pubmed
    ..Our results indicate that Cys-99 and Cys-450 form the only disulfide bond in carboxylase. ..
  38. Mock D, Henrich Shell C, Carnell N, Stumbo P, Mock N. 3-Hydroxypropionic acid and methylcitric acid are not reliable indicators of marginal biotin deficiency in humans. J Nutr. 2004;134:317-20 pubmed
    ..We conclude that none of these organic acids is as sensitive an indicator of marginal biotin deficiency as 3-hydroxyisovaleric acid, which reflects decreased methylcrotonyl-CoA carboxylase. ..
  39. Liu B, Falkenstein Paul H, Schmidt W, Beerhues L. Benzophenone synthase and chalcone synthase from Hypericum androsaemum cell cultures: cDNA cloning, functional expression, and site-directed mutagenesis of two polyketide synthases. Plant J. 2003;34:847-55 pubmed
    ..Site-directed mutagenesis of amino acids shaping the initiation/elongation cavity of CHS yielded a triple mutant (L263M/F265Y/S338G) that preferred benzoyl-CoA over 4-coumaroyl-CoA. ..
  40. Förster Fromme K, Höschle B, Mack C, Bott M, Armbruster W, Jendrossek D. Identification of genes and proteins necessary for catabolism of acyclic terpenes and leucine/isovalerate in Pseudomonas aeruginosa. Appl Environ Microbiol. 2006;72:4819-28 pubmed
    ..A regulatory gene, atuR, was identified upstream of atuABCDEFGH and negatively regulated expression of the atu gene cluster. ..
  41. Stenina O, Pudota B, McNally B, Hommema E, Berkner K. Tethered processivity of the vitamin K-dependent carboxylase: factor IX is efficiently modified in a mechanism which distinguishes Gla's from Glu's and which accounts for comprehensive carboxylation in vivo. Biochemistry. 2001;40:10301-9 pubmed
  42. Ohno M, Yamamoto A, Ono A, Miura G, Funamoto M, Takemoto Y, et al. Influence of clinical and genetic factors on warfarin dose requirements among Japanese patients. Eur J Clin Pharmacol. 2009;65:1097-103 pubmed publisher
    ..The model established in this study might provide us most likely individual maintenance dose based on clinical and genetic backgrounds. ..
  43. Schultz J. HTTM, a horizontally transferred transmembrane domain. Trends Biochem Sci. 2004;29:4-7 pubmed
    ..The conservation of VKGC catalytic sites also indicates an enzymatic function for the other family members. ..
  44. Aguilar J, DIAZ PEREZ C, Díaz Pérez A, Rodríguez Zavala J, Nikolau B, Campos García J. Substrate specificity of the 3-methylcrotonyl coenzyme A (CoA) and geranyl-CoA carboxylases from Pseudomonas aeruginosa. J Bacteriol. 2008;190:4888-93 pubmed publisher
    ..The enzymatic properties of GCCase suggest that it may substitute for MCCase in leucine catabolism and that both the MCCase and GCCase enzymes play important roles in the leucine and acyclic terpene catabolic pathways. ..
  45. Houben R, Jin D, Stafford D, Proost P, Ebberink R, Vermeer C, et al. Osteocalcin binds tightly to the gamma-glutamylcarboxylase at a site distinct from that of the other known vitamin K-dependent proteins. Biochem J. 1999;341 ( Pt 2):265-9 pubmed
    ..From our studies we conclude that descarboxy-osteocalcin must have an internal recognition sequence that binds to gamma-glutamylcarboxylase at a site different from the propeptide-recognition site. ..
  46. Healy S, Heightman T, Hohmann L, Schriemer D, Gravel R. Nonenzymatic biotinylation of histone H2A. Protein Sci. 2009;18:314-28 pubmed publisher
    ..None of the lysine sites within H2A resembles the biotin attachment consensus sequence seen in carboxylases, suggesting a novel mechanism for histone biotinylation. ..
  47. Baumgartner M, Almashanu S, Suormala T, Obie C, Cole R, Packman S, et al. The molecular basis of human 3-methylcrotonyl-CoA carboxylase deficiency. J Clin Invest. 2001;107:495-504 pubmed
    ..We identify five MCCA and nine MCCB mutant alleles and show that missense mutations in each result in loss of function. ..
  48. Che P, Weaver L, Wurtele E, Nikolau B. The role of biotin in regulating 3-methylcrotonyl-coenzyme a carboxylase expression in Arabidopsis. Plant Physiol. 2003;131:1479-86 pubmed
    ..These experiments reveal that in addition to its catalytic role as an enzyme cofactor, biotin has multiple roles in regulating gene expression. ..
  49. Demirev A, Khanal A, Sedai B, Lim S, Na M, Nam D. The role of acyl-coenzyme A carboxylase complex in lipstatin biosynthesis of Streptomyces toxytricini. Appl Microbiol Biotechnol. 2010;87:1129-39 pubmed publisher
    ..5-fold increased in disruptant compared with wild-type. It implies that PccB of S. toxytricini is involved in the activation of octanoic acid to hexylmalonic acid for lipstatin biosynthesis. ..
  50. Lewis B, Rathman S, McMahon R. Dietary biotin intake modulates the pool of free and protein-bound biotin in rat liver. J Nutr. 2001;131:2310-5 pubmed
  51. Camporeale G, Zempleni J, Eissenberg J. Susceptibility to heat stress and aberrant gene expression patterns in holocarboxylase synthetase-deficient Drosophila melanogaster are caused by decreased biotinylation of histones, not of carboxylases. J Nutr. 2007;137:885-9 pubmed
    ..We conclude that gene expression patterns and phenotypes in HCS-deficient flies in previous studies are caused by decreased biotinylation of histones rather than MCC. ..
  52. Muro S, Rodríguez Pombo P, Perez B, Perez Cerda C, Desviat L, Sperl W, et al. Identification of novel mutations in the PCCB gene in European propionic acidemia patients. Mutation in brief no. 253. Online. Hum Mutat. 1999;14:89-90 pubmed
    ..Expression analysis of all these changes will help us to clarify their structural/functional consequences. ..
  53. Chen L, Eriksson N, Gwilliam R, Bentley D, Deloukas P, Wadelius M. Gamma-glutamyl carboxylase (GGCX) microsatellite and warfarin dosing. Blood. 2005;106:3673-4 pubmed