2r3v

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The Biochemical and Structural Basis for Feedback Inhibition of Mevalonate Kinase and Isoprenoid Metabolism

Structural highlights

2r3v is a 4 chain structure with sequence from Homo sapiens. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance.
Method:X-ray diffraction, Resolution 2.5Å
Resources:FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT

Disease

KIME_HUMAN Defects in MVK are the cause of mevalonic aciduria (MEVA) [MIM:610377. It is an accumulation of mevalonic acid which causes a variety of symptoms such as psychomotor retardation, dysmorphic features, cataracts, hepatosplenomegaly, lymphadenopathy, anemia, hypotonia, myopathy, and ataxia.[1] [2] [3] [4] [5] Defects in MVK are the cause of hyperimmunoglobulinemia D and periodic fever syndrome (HIDS) [MIM:260920. HIDS is an autosomal recessive disease characterized by recurrent episodes of unexplained high fever associated with skin rash, diarrhea, adenopathy (swollen, tender lymph nodes), athralgias and/or arthritis. Concentration of IgD, and often IgA, are above normal.[6] [7] [8] [9] [10]

Function

KIME_HUMAN May be a regulatory site in cholesterol biosynthetic pathway.

Evolutionary Conservation

Check, as determined by ConSurfDB. You may read the explanation of the method and the full data available from ConSurf.

Publication Abstract from PubMed

Mevalonate kinase (MK), which catalyzes a key reaction in polyisoprenoid and sterol metabolism in many organisms, is subject to feedback regulation by farnesyl diphosphate and related compounds. The structures of human mevalonate kinase and a binary complex of the rat enzyme incubated with farnesyl thiodiphosphate (FSPP) are reported. Significant FSPP hydrolysis occurs under crystallization conditions; this results in detection of farnesyl thiophosphate (FSP) in the structure of the binary complex. Farnesyl thiodiphosphate competes with substrate ATP to produce feedback inhibition of mevalonate kinase. The binding sites for these metabolites overlap, with the phosphate of FSP nearly superimposed on ATP's beta-phosphate and FSP's polyisoprenoid chain overlapping ATP's adenosine moiety. Several hydrophobic amino acid side chains are positioned near the polyisoprenoid chain of FSP and their functional significance has been evaluated in mutagenesis experiments with human MK, which exhibits the highest reported sensitivity to feedback inhibition. Results suggest that single and double mutations at T104 and I196 produce a significant inflation of the K(i) for FSPP (approximately 40-fold for T104A/I196A). Such an effect persists when K(i) values are normalized for effects on the K(m) for ATP, suggesting that it may be possible to engineer MK proteins with altered sensitivity to feedback inhibition. Comparison of animal MK protein alignments and structures with those of a MK protein from Streptococcus pneumoniae indicates that sequence differences between N- and C-terminal domains correlate with differences in interdomain angles. Bacterial MK proteins exhibit more solvent exposure of feedback inhibitor binding sites and, consequently, weaker binding of these inhibitors.

Biochemical and structural basis for feedback inhibition of mevalonate kinase and isoprenoid metabolism.,Fu Z, Voynova NE, Herdendorf TJ, Miziorko HM, Kim JJ Biochemistry. 2008 Mar 25;47(12):3715-24. Epub 2008 Feb 27. PMID:18302342[11]

From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.

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Citations
4 reviews cite this structure
Enzymes of the mevalonate pathway of isoprenoid biosynthesis.
Miziorko et al. (2011)
3 more
12 other articles
No citations found

See Also

References

  1. ↑ Schafer BL, Bishop RW, Kratunis VJ, Kalinowski SS, Mosley ST, Gibson KM, Tanaka RD. Molecular cloning of human mevalonate kinase and identification of a missense mutation in the genetic disease mevalonic aciduria. J Biol Chem. 1992 Jul 5;267(19):13229-38. PMID:1377680
  2. ↑ Houten SM, Koster J, Romeijn GJ, Frenkel J, Di Rocco M, Caruso U, Landrieu P, Kelley RI, Kuis W, Poll-The BT, Gibson KM, Wanders RJ, Waterham HR. Organization of the mevalonate kinase (MVK) gene and identification of novel mutations causing mevalonic aciduria and hyperimmunoglobulinaemia D and periodic fever syndrome. Eur J Hum Genet. 2001 Apr;9(4):253-9. PMID:11313768 doi:10.1038/sj.ejhg.5200595
  3. ↑ Hinson DD, Ross RM, Krisans S, Shaw JL, Kozich V, Rolland MO, Divry P, Mancini J, Hoffmann GF, Gibson KM. Identification of a mutation cluster in mevalonate kinase deficiency, including a new mutation in a patient of Mennonite ancestry. Am J Hum Genet. 1999 Aug;65(2):327-35. PMID:10417275 doi:S0002-9297(07)62049-7
  4. ↑ Houten SM, Romeijn GJ, Koster J, Gray RG, Darbyshire P, Smit GP, de Klerk JB, Duran M, Gibson KM, Wanders RJ, Waterham HR. Identification and characterization of three novel missense mutations in mevalonate kinase cDNA causing mevalonic aciduria, a disorder of isoprene biosynthesis. Hum Mol Genet. 1999 Aug;8(8):1523-8. PMID:10401001
  5. ↑ Cuisset L, Drenth JP, Simon A, Vincent MF, van der Velde Visser S, van der Meer JW, Grateau G, Delpech M. Molecular analysis of MVK mutations and enzymatic activity in hyper-IgD and periodic fever syndrome. Eur J Hum Genet. 2001 Apr;9(4):260-6. PMID:11313769 doi:10.1038/sj.ejhg.5200614
  6. ↑ Houten SM, Koster J, Romeijn GJ, Frenkel J, Di Rocco M, Caruso U, Landrieu P, Kelley RI, Kuis W, Poll-The BT, Gibson KM, Wanders RJ, Waterham HR. Organization of the mevalonate kinase (MVK) gene and identification of novel mutations causing mevalonic aciduria and hyperimmunoglobulinaemia D and periodic fever syndrome. Eur J Hum Genet. 2001 Apr;9(4):253-9. PMID:11313768 doi:10.1038/sj.ejhg.5200595
  7. ↑ Cuisset L, Drenth JP, Simon A, Vincent MF, van der Velde Visser S, van der Meer JW, Grateau G, Delpech M. Molecular analysis of MVK mutations and enzymatic activity in hyper-IgD and periodic fever syndrome. Eur J Hum Genet. 2001 Apr;9(4):260-6. PMID:11313769 doi:10.1038/sj.ejhg.5200614
  8. ↑ Houten SM, Kuis W, Duran M, de Koning TJ, van Royen-Kerkhof A, Romeijn GJ, Frenkel J, Dorland L, de Barse MM, Huijbers WA, Rijkers GT, Waterham HR, Wanders RJ, Poll-The BT. Mutations in MVK, encoding mevalonate kinase, cause hyperimmunoglobulinaemia D and periodic fever syndrome. Nat Genet. 1999 Jun;22(2):175-7. PMID:10369261 doi:10.1038/9691
  9. ↑ Drenth JP, Cuisset L, Grateau G, Vasseur C, van de Velde-Visser SD, de Jong JG, Beckmann JS, van der Meer JW, Delpech M. Mutations in the gene encoding mevalonate kinase cause hyper-IgD and periodic fever syndrome. International Hyper-IgD Study Group. Nat Genet. 1999 Jun;22(2):178-81. PMID:10369262 doi:10.1038/9696
  10. ↑ D'Osualdo A, Picco P, Caroli F, Gattorno M, Giacchino R, Fortini P, Corona F, Tommasini A, Salvi G, Specchia F, Obici L, Meini A, Ricci A, Seri M, Ravazzolo R, Martini A, Ceccherini I. MVK mutations and associated clinical features in Italian patients affected with autoinflammatory disorders and recurrent fever. Eur J Hum Genet. 2005 Mar;13(3):314-20. PMID:15536479 doi:5201323
  11. ↑ Fu Z, Voynova NE, Herdendorf TJ, Miziorko HM, Kim JJ. Biochemical and structural basis for feedback inhibition of mevalonate kinase and isoprenoid metabolism. Biochemistry. 2008 Mar 25;47(12):3715-24. Epub 2008 Feb 27. PMID:18302342 doi:10.1021/bi7024386

Contents


PDB ID 2r3v

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