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Gene Review

IVD  -  isovaleryl-CoA dehydrogenase

Homo sapiens

Synonyms: ACAD2, Isovaleryl-CoA dehydrogenase, mitochondrial
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Disease relevance of IVD

  • The mutant IVD precursor is imported and processed to mature size, but no active enzyme is detected in mutant fibroblasts or expressed in Escherichia coli [1].
  • Endocrine function was prospectively evaluated in 98 patients (73 men and 25 women) infected by HIV in various stages of illness: Centers for Disease Control groups II (19), III (20), IVA and IVC2 (27), IVC1 and IVD (32) [2].
  • Although some patients with AIDS Centers for Disease Control (CDC) group IVC and IVD have the lowest responses, asymptomatic (CDC group II) and AIDS-related complex (ARC; CDC groups III/IVA and IVB) patients also show significant defects [3].
  • Patients with clinically nonsymptomatic cirrhosis (histology activity index IVD; Child A) metabolized 13C-methacetin to a significantly lesser extent (delta over baseline values of the patients at 15 min: 8.3 +/- 4.9 per thousand; P < 0.005 and cumulative recovery after 30 min: 5.6 +/- 3.2%; P < 0.003) [4].
  • During the 12 hours when most alkali therapy was given, babies dying with IVD received a mean total alkali dosage of 10-21 mmol/kg and those dying without IVH 6-34 mmol/kg (P less than 0-001).There was no difference in severity of hypoxia or of metabolic acidosis between the 2 groups [5].

Psychiatry related information on IVD


High impact information on IVD

  • In the Northern blot analysis of normal human liver and fibroblast poly(A)+ RNA, three mRNA species of different sizes (4.6, 3.8, and 2.1 kb) hybridized to IVD cDNA [11].
  • We isolated five overlapping IVD cDNA clones from a human placenta cDNA library [11].
  • Isovaleric acidemia, resulting from isovaleryl-coenzyme A dehydrogenase deficiency, is associated with marked reduction of free carnitine in both plasma and urine [12].
  • Molecular genetic analysis of the IVD gene for 19 subjects whose condition was detected through NBS led to the identification of one recurring mutation, 932C-->T (A282V), in 47% of mutant alleles [13].
  • Another cell line (IVD) was deficient in the deacetylation of PI-GlcNAc to form PI-GlcN and subsequent mannosylated species [14].

Chemical compound and disease context of IVD


Biological context of IVD

  • In order to further study these mutations at the molecular level, the IVD coding region from mutant fibroblast cDNA was amplified by the PCR and was analyzed by DNA sequencing. cDNA from class I mutant alleles from two of seven class I mutant cell lines each contained a different missense mutation [16].
  • We have previously identified a nucleotide deletion in the gene for IVD in fibroblasts from a patient with isovaleric acidemia leading to a shift in reading frame and premature termination of translation [1].
  • This deletion is caused by an error in RNA splicing and predicts the in-frame deletion of 30 amino acids beginning with leucine 20 of the mature IVD [17].
  • Importantly, a dimeric intermediate in the folding pathway for wild type IVD has been identified in the in vitro mitochondrial import experiments, the first report of such an intermediate in the biogenesis of an acyl-CoA dehydrogenase [1].
  • To understand this dichotomy and to gain a better understanding of the factors important in determining substrate specificity in this enzyme family, the three-dimensional structure of human IVD has been determined [18].

Anatomical context of IVD

  • IVD is produced as a 45-kDa precursor and then is transported into the mitochondria, where it is processed to its mature 43-kDa size [16].
  • Purification and characterization of isovaleryl coenzyme A dehydrogenase from rat liver mitochondria [19].
  • In the future, a series of vectors with multiple genes that are regulated by physiologic cues might be used to enhance spinal fusion, restore IVD tissue, or support spinal cord healing [20].
  • Moreover, this study confirmed that the interstitial fluid pressurization plays an important role in the load support mechanism of IVD by sharing more than 40% of the total load during disc compression [21].
  • The involvement of cytokines and other inflammatory mediators in the generation of vascularization and stimulation of pain receptors are still controversial but may reveal the pathway to the symptomatic conditions of IVD degeneration [22].

Associations of IVD with chemical compounds


Regulatory relationships of IVD

  • According to a multiple regression analysis, the progression to stages IVB, IVC1 or IVD of the Centers for Disease Control (CDC) appeared to be the main explanatory variable in free protein S-deficient patients [24].

Other interactions of IVD

  • Using the polymerase chain reaction, we have identified a 90-base pair deletion encompassing bases 145-234 in type II IVD cDNA [17].
  • Polymers IVD, VD and VID were incubated with interferon (IFN) to obtain complexes: carrier-IFN [25].
  • Site-directed mutagenesis was used to match the human IVD active site with that of potato 2MBCD [26].
  • The plasma protein S (PS) system was studied in 120 HIV seropositive patients (CDC classification: group II: n = 35; group III: n = 6; groups IVA, IVC2 or IVE, n = 38; groups IVB, IVC1 or IVD, n = 41) [27].
  • We concluded that protein turnover is an important determinant of pentosidine accumulation in aggrecan and collagen of human IVD, as was found for articular cartilage [28].

Analytical, diagnostic and therapeutic context of IVD

  • Western blotting, in vitro mitochondrial import, prokaryotic expression, and kinetic studies of IVD mutants were conducted to characterize the molecular defects caused by the amino acid replacements [29].
  • Circular dichroism studies substantiated our earlier findings that both SCAD E368G and IVD E254G are unable to form a charge-transfer complex with substrate/product [30].
  • The Quantikine IVD EPO ELISA (R&D Systems, Inc.) is based on the double-antibody sandwich method [31].
  • CONCLUSIONS: These results demonstrate that this method for detecting MC-CoA production, using HPLC, is a practical assay for determining IVD activity [32].
  • Finally, the high throughput technologies, such as the gene chip, are elucidating thousands of genes that may be good candidates for the enhancement of bone healing and IVD and spinal cord regeneration [20].


  1. Mitochondrial import and processing of wild type and type III mutant isovaleryl-CoA dehydrogenase. Volchenboum, S.L., Vockley, J. J. Biol. Chem. (2000) [Pubmed]
  2. Endocrine function in 98 HIV-infected patients: a prospective study. Raffi, F., Brisseau, J.M., Planchon, B., Rémi, J.P., Barrier, J.H., Grolleau, J.Y. AIDS (1991) [Pubmed]
  3. Response of mononuclear cells from HIV-infected patients to B-cell mitogens: correlation with immunological and clinical features of disease progression. Edelman, A.S., Zolla-Pazner, S. AIDS (1990) [Pubmed]
  4. 13C-methacetin breath test as liver function test in patients with chronic hepatitis C virus infection. Braden, B., Faust, D., Sarrazin, U., Zeuzem, S., Dietrich, C.F., Caspary, W.F., Sarrazin, C. Aliment. Pharmacol. Ther. (2005) [Pubmed]
  5. Hyaline membrane disease, alkali, and intraventricular haemorrhage. Wigglesworth, J.S., Keith, I.H., Girling, D.J., Slade, S.A. Arch. Dis. Child. (1976) [Pubmed]
  6. Characterizing alterations in executive functioning across distinct subtypes of cortical and subcortical dementia. Lamar, M., Swenson, R., Kaplan, E., Libon, D.J. The Clinical neuropsychologist. (2004) [Pubmed]
  7. Error analysis of the nine-word California Verbal Learning Test (CVLT-9) among older adults with and without dementia. Davis, K.L., Price, C.C., Kaplan, E., Libon, D.J. The Clinical neuropsychologist. (2002) [Pubmed]
  8. Evaluation of IVD simulations to determine problem-solving practice capability. Klaassens, E. Nursing educators microworld. (1993) [Pubmed]
  9. Dementia associated with periventricular and deep white matter alterations: a subtype of subcortical dementia. Libon, D.J., Bogdanoff, B., Bonavita, J., Skalina, S., Cloud, B.S., Resh, R., Cass, P., Ball, S.K. Archives of clinical neuropsychology : the official journal of the National Academy of Neuropsychologists. (1997) [Pubmed]
  10. A study of Hiv/STD infections amongst commercial sex workers in Kolkata (India). Part-II: sexual behaviour, knowledge and attitude towards STD/HIV infections. Raut, D.K., Pal, D., Das, A. The Journal of communicable diseases. (2003) [Pubmed]
  11. Nucleotide sequence of messenger RNA encoding human isovaleryl-coenzyme A dehydrogenase and its expression in isovaleric acidemia fibroblasts. Matsubara, Y., Ito, M., Glassberg, R., Satyabhama, S., Ikeda, Y., Tanaka, K. J. Clin. Invest. (1990) [Pubmed]
  12. L-carnitine therapy in isovaleric acidemia. Roe, C.R., Millington, D.S., Maltby, D.A., Kahler, S.G., Bohan, T.P. J. Clin. Invest. (1984) [Pubmed]
  13. A common mutation is associated with a mild, potentially asymptomatic phenotype in patients with isovaleric acidemia diagnosed by newborn screening. Ensenauer, R., Vockley, J., Willard, J.M., Huey, J.C., Sass, J.O., Edland, S.D., Burton, B.K., Berry, S.A., Santer, R., Grünert, S., Koch, H.G., Marquardt, I., Rinaldo, P., Hahn, S., Matern, D. Am. J. Hum. Genet. (2004) [Pubmed]
  14. Stimulation of glycogen synthesis by insulin in human erythroleukemia cells requires the synthesis of glycosyl-phosphatidylinositol. Lazar, D.F., Knez, J.J., Medof, M.E., Cuatrecasas, P., Saltiel, A.R. Proc. Natl. Acad. Sci. U.S.A. (1994) [Pubmed]
  15. The leucine-responsive regulatory protein (Lrp) acts as a specific repressor for sigma s-dependent transcription of the Escherichia coli aidB gene. Landini, P., Hajec, L.I., Nguyen, L.H., Burgess, R.R., Volkert, M.R. Mol. Microbiol. (1996) [Pubmed]
  16. Molecular characterization of four different classes of mutations in the isovaleryl-CoA dehydrogenase gene responsible for isovaleric acidemia. Vockley, J., Parimoo, B., Tanaka, K. Am. J. Hum. Genet. (1991) [Pubmed]
  17. The variant human isovaleryl-CoA dehydrogenase gene responsible for type II isovaleric acidemia determines an RNA splicing error, leading to the deletion of the entire second coding exon and the production of a truncated precursor protein that interacts poorly with mitochondrial import receptors. Vockley, J., Nagao, M., Parimoo, B., Tanaka, K. J. Biol. Chem. (1992) [Pubmed]
  18. Structure of human isovaleryl-CoA dehydrogenase at 2.6 A resolution: structural basis for substrate specificity,. Tiffany, K.A., Roberts, D.L., Wang, M., Paschke, R., Mohsen, A.W., Vockley, J., Kim, J.J. Biochemistry (1997) [Pubmed]
  19. Purification and characterization of isovaleryl coenzyme A dehydrogenase from rat liver mitochondria. Ikeda, Y., Tanaka, K. J. Biol. Chem. (1983) [Pubmed]
  20. Gene therapy for spinal applications. Hidaka, C., Khan, S.N., Farmer, J.C., Sandhu, H.S. Orthop. Clin. North Am. (2002) [Pubmed]
  21. Physical signals and solute transport in human intervertebral disc during compressive stress relaxation: 3D finite element analysis. Yao, H., Gu, W.Y. Biorheology. (2006) [Pubmed]
  22. The molecular basis of intervertebral disk degeneration. Chung, S.A., Khan, S.N., Diwan, A.D. Orthop. Clin. North Am. (2003) [Pubmed]
  23. Identification of the active site catalytic residue in human isovaleryl-CoA dehydrogenase. Mohsen, A.W., Vockley, J. Biochemistry (1995) [Pubmed]
  24. Acquired protein S deficiency: correlation with advanced disease in HIV-1-infected patients. Bissuel, F., Berruyer, M., Causse, X., Dechavanne, M., Trepo, C. J. Acquir. Immune Defic. Syndr. (1992) [Pubmed]
  25. 1,4-naphthoquinone-2-sulfonic acid derivatives coupled to dextran as carriers for interferon. Piasecki, E., Charytonowicz, D., Konieczny, M., Inglot, A.D. Arch. Immunol. Ther. Exp. (Warsz.) (1988) [Pubmed]
  26. Convergent evolution of a 2-methylbutyryl-CoA dehydrogenase from isovaleryl-CoA dehydrogenase in Solanum tuberosum. Goetzman, E.S., Mohsen, A.W., Prasad, K., Vockley, J. J. Biol. Chem. (2005) [Pubmed]
  27. Study of the protein S system in HIV-infected patients: acquired protein S deficiency or unsuitable assays? Schved, J.F., Gris, J.C., Michaud, A., Amiral, J., Quincat, D., Arnaud, A., Martinez, P. Blood Coagul. Fibrinolysis (1992) [Pubmed]
  28. Age-related accumulation of pentosidine in aggrecan and collagen from normal and degenerate human intervertebral discs. Sivan, S.S., Tsitron, E., Wachtel, E., Roughley, P., Sakkee, N., van der Ham, F., Degroot, J., Maroudas, A. Biochem. J. (2006) [Pubmed]
  29. Characterization of molecular defects in isovaleryl-CoA dehydrogenase in patients with isovaleric acidemia. Mohsen, A.W., Anderson, B.D., Volchenboum, S.L., Battaile, K.P., Tiffany, K., Roberts, D., Kim, J.J., Vockley, J. Biochemistry (1998) [Pubmed]
  30. Functional analysis of acyl-CoA dehydrogenase catalytic residue mutants using surface plasmon resonance and circular dichroism. Goetzman, E.S., He, M., Nguyen, T.V., Vockley, J. Mol. Genet. Metab. (2006) [Pubmed]
  31. The value of serum levels of IL-6, TNF-alpha, and erythropoietin in metastatic malignant melanoma: serum IL-6 level is a valuable prognostic factor at least as serum LDH in advanced melanoma. Tas, F., Oguz, H., Argon, A., Duranyildiz, D., Camlica, H., Yasasever, V., Topuz, E. Med. Oncol. (2005) [Pubmed]
  32. Establishment of a practical enzymatic assay method for determination of isovaleryl-CoA dehydrogenase activity using high-performance liquid chromatography. Tajima, G., Sakura, N., Yofune, H., Dwi Bahagia Febriani, A., Nishimura, Y., Sakamoto, A., Ono, H., Shigematsu, Y., Kobayashi, M. Clin. Chim. Acta (2005) [Pubmed]
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