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Gene Review

PLOD1  -  procollagen-lysine, 2-oxoglutarate 5...

Homo sapiens

Synonyms: EDS6, LH, LH1, LLH, Lysyl hydroxylase 1, ...
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Disease relevance of PLOD1

  • Mutation analysis of the PLOD1 gene: an efficient multistep approach to the molecular diagnosis of the kyphoscoliotic type of Ehlers-Danlos syndrome (EDS VIA) [1].
  • Recombinant lysyl hydroxylase 3 expressed in insect cells by means of a baculovirus vector was found to be more soluble than lysyl hydroxylase 1 expressed in the same cell type [2].
  • Identification of PLOD2 as telopeptide lysyl hydroxylase, an important enzyme in fibrosis [3].
  • We took as a template for the design sphbeta31, a truncated 31 amino acid analogue of the native beta-apoprotein from the core LH complex of Rhodobacter sphaeroides [4].
  • Additionally, we have compared the self-assembly of sphbeta31 and LH1beta24 with BChls and discovered that the association enthalpies and entropies of both species are similar to those measured for native LH1 from Rhodospirillum rubrum [4].

High impact information on PLOD1

  • Mutations in the genes encoding the major fibrillar collagen types I and III have been demonstrated in EDS types VII and IV, respectively, while mutations in the lysyl hydroxylase and ATP7A genes, with roles in collagen cross-linking, are responsible for EDS types VI and IX [5].
  • The mutation leads to an almost complete absence of lysyl hydroxylase activity in extracts derived from fibroblasts of the patients [6].
  • A homozygous stop codon in the lysyl hydroxylase gene in two siblings with Ehlers-Danlos syndrome type VI [6].
  • EDS type VI was the first connective tissue disorder for which a specific defect in collagen metabolism was identified, namely a deficiency of lysyl hydroxylase activity [6].
  • Here, we report on the positional cloning of diwanka and show that it encodes LH3, a myotomally expressed multifunctional enzyme with lysyl hydroxylase and glycosyltransferase domains [7].

Chemical compound and disease context of PLOD1


Biological context of PLOD1

  • In contrast to the PLOD1 and PLOD3 genes, both cell types showed low PLOD2 gene expression in undifferentiated and early differentiated conditions [13].
  • To understand the functions of the four molecular forms of LH in vertebrates, we analyzed differences in the binding and hydroxylation of various collagenous peptides by the LH isoforms [14].
  • The data suggest that the LH binding site is not a deep hydrophobic pocket but is open and hydrophilic where acidic amino acids play an important role in the binding [14].
  • Lysyl hydroxylase (EC ) and glucosyltransferase (EC ) are enzymes involved in post-translational modifications during collagen biosynthesis [15].
  • This study describes 3 patients with mixed phenotypes of EDS, who have significantly decreased mRNAs for LH2, but normal levels of LH1 and LH3 mRNAs, in their skin fibroblasts [16].

Anatomical context of PLOD1


Associations of PLOD1 with chemical compounds


Physical interactions of PLOD1

  • Structural analysis of crystallized peripheral (LH2) and core antenna complexes (LH1) of purple bacteria has revealed circular aggregates of high rotational symmetry (C8, C9 and C16, respectively) [20].

Regulatory relationships of PLOD1


Other interactions of PLOD1

  • High levels of PLOD1 and PLOD3 genes were expressed in both BMSCs and NSFs, and the expression levels did not change in the course of differentiation [13].
  • Plod-2, as well as the human PLOD-1 promoters, contains multiple bicoid (PITX2) binding elements [21].
  • In a patient population (n = 104) of European descent, there were four SNPs within TNFRSF1B and six SNPs within PLOD1 that occurred with greater than 5% frequency [23].
  • Lysyl hydroxylase (EC, a homodimer, catalyzes the formation of hydroxylysine in collagens [2].
  • Moreover, the unique action of minoxidil in specifically decreasing LH mRNAs contrasts with the less specific stimulatory effects of hydralazine and suggests that these pharmaceuticals are regulating expression of LH at a pretranslational level by different mechanisms [24].

Analytical, diagnostic and therapeutic context of PLOD1


  1. Mutation analysis of the PLOD1 gene: an efficient multistep approach to the molecular diagnosis of the kyphoscoliotic type of Ehlers-Danlos syndrome (EDS VIA). Giunta, C., Randolph, A., Steinmann, B. Mol. Genet. Metab. (2005) [Pubmed]
  2. Cloning and characterization of a third human lysyl hydroxylase isoform. Passoja, K., Rautavuoma, K., Ala-Kokko, L., Kosonen, T., Kivirikko, K.I. Proc. Natl. Acad. Sci. U.S.A. (1998) [Pubmed]
  3. Identification of PLOD2 as telopeptide lysyl hydroxylase, an important enzyme in fibrosis. van der Slot, A.J., Zuurmond, A.M., Bardoel, A.F., Wijmenga, C., Pruijs, H.E., Sillence, D.O., Brinckmann, J., Abraham, D.J., Black, C.M., Verzijl, N., DeGroot, J., Hanemaaijer, R., TeKoppele, J.M., Huizinga, T.W., Bank, R.A. J. Biol. Chem. (2003) [Pubmed]
  4. Design of a minimal polypeptide unit for bacteriochlorophyll binding and self-assembly based on photosynthetic bacterial light-harvesting proteins. Noy, D., Dutton, P.L. Biochemistry (2006) [Pubmed]
  5. A translocation interrupts the COL5A1 gene in a patient with Ehlers-Danlos syndrome and hypomelanosis of Ito. Toriello, H.V., Glover, T.W., Takahara, K., Byers, P.H., Miller, D.E., Higgins, J.V., Greenspan, D.S. Nat. Genet. (1996) [Pubmed]
  6. A homozygous stop codon in the lysyl hydroxylase gene in two siblings with Ehlers-Danlos syndrome type VI. Hyland, J., Ala-Kokko, L., Royce, P., Steinmann, B., Kivirikko, K.I., Myllylä, R. Nat. Genet. (1992) [Pubmed]
  7. The myotomal diwanka (lh3) glycosyltransferase and type XVIII collagen are critical for motor growth cone migration. Schneider, V.A., Granato, M. Neuron (2006) [Pubmed]
  8. The kyphoscoliotic type of Ehlers-Danlos syndrome (type VI): differential effects on the hydroxylation of lysine in collagens I and II revealed by analysis of cross-linked telopeptides from urine. Eyre, D., Shao, P., Weis, M.A., Steinmann, B. Mol. Genet. Metab. (2002) [Pubmed]
  9. Deletion of cysteine 369 in lysyl hydroxylase 1 eliminates enzyme activity and causes Ehlers-Danlos syndrome type VI. Yeowell, H.N., Allen, J.D., Walker, L.C., Overstreet, M.A., Murad, S., Thai, S.F. Matrix Biol. (2000) [Pubmed]
  10. Ehlers-Danlos syndrome in two siblings with deficient lysyl hydroxylase activity in cultured skin fibroblasts but only mild hydroxylysine deficit in skin. Steinmann, B., Gitzelmann, R., Vogel, A., Grant, M.E., Harwood, R., Sear, C.H. Helvetica paediatrica acta. (1975) [Pubmed]
  11. An upstream region of the rat luteinizing hormone beta gene binds estrogen receptor and confers estrogen responsiveness. Shupnik, M.A., Weinmann, C.M., Notides, A.C., Chin, W.W. J. Biol. Chem. (1989) [Pubmed]
  12. A novel mutation of the luteinizing hormone receptor gene causing male gonadotropin-independent precocious puberty. Latronico, A.C., Anasti, J., Arnhold, I.J., Mendonça, B.B., Domenice, S., Albano, M.C., Zachman, K., Wajchenberg, B.L., Tsigos, C. J. Clin. Endocrinol. Metab. (1995) [Pubmed]
  13. Differential expression of human lysyl hydroxylase genes, lysine hydroxylation, and cross-linking of type I collagen during osteoblastic differentiation in vitro. Uzawa, K., Grzesik, W.J., Nishiura, T., Kuznetsov, S.A., Robey, P.G., Brenner, D.A., Yamauchi, M. J. Bone Miner. Res. (1999) [Pubmed]
  14. Characterization of collagenous peptides bound to lysyl hydroxylase isoforms. Risteli, M., Niemitalo, O., Lankinen, H., Juffer, A.H., Myllylä, R. J. Biol. Chem. (2004) [Pubmed]
  15. Lysyl hydroxylase 3 is a multifunctional protein possessing collagen glucosyltransferase activity. Heikkinen, J., Risteli, M., Wang, C., Latvala, J., Rossi, M., Valtavaara, M., Myllylä, R. J. Biol. Chem. (2000) [Pubmed]
  16. Decreased expression of lysyl hydroxylase 2 (LH2) in skin fibroblasts from three Ehlers-Danlos patients does not result from mutations in either the coding or proximal promoter region of the LH2 gene. Walker, L.C., Teebi, A.S., Marini, J.C., De Paepe, A., Malfait, F., Atsawasuwan, P., Yamauchi, M., Yeowell, H.N. Mol. Genet. Metab. (2004) [Pubmed]
  17. Cloning and characterization of a novel human lysyl hydroxylase isoform highly expressed in pancreas and muscle. Valtavaara, M., Papponen, H., Pirttilä, A.M., Hiltunen, K., Helander, H., Myllylä, R. J. Biol. Chem. (1997) [Pubmed]
  18. A single C-terminal peptide segment mediates both membrane association and localization of lysyl hydroxylase in the endoplasmic reticulum. Suokas, M., Myllyla, R., Kellokumpu, S. J. Biol. Chem. (2000) [Pubmed]
  19. Characterization of three fragments that constitute the monomers of the human lysyl hydroxylase isoenzymes 1-3. The 30-kDa N-terminal fragment is not required for lysyl hydroxylase activity. Rautavuoma, K., Takaluoma, K., Passoja, K., Pirskanen, A., Kvist, A.P., Kivirikko, K.I., Myllyharju, J. J. Biol. Chem. (2002) [Pubmed]
  20. Pigment-protein architecture in the light-harvesting antenna complexes of purple bacteria: does the crystal structure reflect the native pigment-protein arrangement? Leupold, D., Voigt, B., Beenken, W., Stiel, H. FEBS Lett. (2000) [Pubmed]
  21. PITX2 regulates procollagen lysyl hydroxylase (PLOD) gene expression: implications for the pathology of Rieger syndrome. Hjalt, T.A., Amendt, B.A., Murray, J.C. J. Cell Biol. (2001) [Pubmed]
  22. Transforming growth factor beta 1 influences lysyl hydroxylation of collagen I and reduces steady-state levels of lysyl hydroxylase mRNA in human osteoblast-like cells. Seitzer, U., Bätge, B., Acil, Y., Müller, P.K. Eur. J. Clin. Invest. (1995) [Pubmed]
  23. Association analysis of bone mineral density and single nucleotide polymorphisms in two candidate genes on chromosome 1p36. Spotila, L.D., Rodriguez, H., Koch, M., Tenenhouse, H.S., Tenenhouse, A., Li, H., Devoto, M. Calcif. Tissue Int. (2003) [Pubmed]
  24. Characterization of a partial cDNA for lysyl hydroxylase from human skin fibroblasts; lysyl hydroxylase mRNAs are regulated differently by minoxidil derivatives and hydralazine. Yeowell, H.N., Ha, V., Walker, L.C., Murad, S., Pinnell, S.R. J. Invest. Dermatol. (1992) [Pubmed]
  25. A patient with Ehlers-Danlos syndrome type VI is a compound heterozygote for mutations in the lysyl hydroxylase gene. Ha, V.T., Marshall, M.K., Elsas, L.J., Pinnell, S.R., Yeowell, H.N. J. Clin. Invest. (1994) [Pubmed]
  26. Intracellular enzymes of collagen biosynthesis in human platelets. Anttinen, H., Tuderman, L., Oikarinen, A., Kivirikko, K.I. Blood (1977) [Pubmed]
  27. Site-directed mutagenesis of human lysyl hydroxylase expressed in insect cells. Identification of histidine residues and an aspartic acid residue critical for catalytic activity. Pirskanen, A., Kaimio, A.M., Myllylä, R., Kivirikko, K.I. J. Biol. Chem. (1996) [Pubmed]
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