Genomes and Genes
2 oxoglutarate 5 dioxygenase procollagen lysine
Summary: A mixed-function oxygenase that catalyzes the hydroxylation of peptidyllysine, usually in protocollagen, to peptidylhydroxylysine. The enzyme utilizes molecular oxygen with concomitant oxidative decarboxylation of the cosubstrate 2-oxoglutarate to succinate. EC 220.127.116.11.
- Oh J, Krapfenbauer K, Lubec G. Proteomic identification of collagens and related proteins in human fibroblasts. Amino Acids. 2004;27:305-11 pubmed
- Salo A, Wang C, Sipilä L, Sormunen R, Vapola M, Kervinen P, et al. Lysyl hydroxylase 3 (LH3) modifies proteins in the extracellular space, a novel mechanism for matrix remodeling. J Cell Physiol. 2006;207:644-53 pubmed
- Jenniskens Y, Koevoet W, de Bart A, Weinans H, Jahr H, Verhaar J, et al. Biochemical and functional modulation of the cartilage collagen network by IGF1, TGFbeta2 and FGF2. Osteoarthritis Cartilage. 2006;14:1136-46 pubmed..Of the three growth factors tested, IGF1 seems to be best in promoting the formation of a functional collagen network since it increased proteoglycan and collagen deposition and improved the mechanical properties. ..
- Takashi M, Tsubaki S, Tsuzuki T, Duarte W, Yamauchi M, Sato H. Differential gene expression of collagen-binding small leucine-rich proteoglycans and lysyl hydroxylases, during mineralization by MC3T3-E1 cells cultured on titanium implant material. Eur J Oral Sci. 2005;113:225-31 pubmed..LH3 was maintained at a steady level throughout. This study suggests actual but distinct roles of SLRPs and LHs in the formation of a unique ultrastructure at the bone-implant interface. ..
- Simard A, Di Giorgio L, Amen M, Westwood A, Amendt B, Ryan A. The Pitx2c N-terminal domain is a critical interaction domain required for asymmetric morphogenesis. Dev Dyn. 2009;238:2459-70 pubmed publisher..Our data suggest that the Pitx2c N-terminal domain competes with endogenous Pitx2c for binding to a protein interaction partner that is required for the activation of genes that direct asymmetric morphogenesis along the left-right axis. ..
- Saha S, Ghosh P, Konar A, Bhattacharya S, Roy S. Differential expression of procollagen lysine 2-oxoglutarate 5-deoxygenase and matrix metalloproteinase isoforms in hypothyroid rat ovary and disintegration of extracellular matrix. Endocrinology. 2005;146:2963-75 pubmed
- Saito M, Fujii K, Tanaka T, Soshi S. Effect of low- and high-intensity pulsed ultrasound on collagen post-translational modifications in MC3T3-E1 osteoblasts. Calcif Tissue Int. 2004;75:384-95 pubmed
- Chen Y, Terajima M, Banerjee P, Guo H, Liu X, Yu J, et al. FKBP65-dependent peptidyl-prolyl isomerase activity potentiates the lysyl hydroxylase 2-driven collagen cross-link switch. Sci Rep. 2017;7:46021 pubmed publisher..Because LH2 promotes fibrosis and cancer metastasis, our findings suggest that pharmacologic strategies to target FKBP65 and LH2 may have complementary therapeutic activities. ..
- Ulrich M, Verkerk M, Reijnen L, Vlig M, van den Bogaerdt A, Middelkoop E. Expression profile of proteins involved in scar formation in the healing process of full-thickness excisional wounds in the porcine model. Wound Repair Regen. 2007;15:482-90 pubmed..Moreover, the expression of the putative gene responsible for this type of cross-linking, the lysyl hydroxylase-2b, is elevated during wound healing. ..
- Pornprasertsuk S, Duarte W, Mochida Y, Yamauchi M. Overexpression of lysyl hydroxylase-2b leads to defective collagen fibrillogenesis and matrix mineralization. J Bone Miner Res. 2005;20:81-7 pubmed..These results indicate a critical role of LH2b catalyzed post-translational modification of collagen (i.e., telopeptidyl lysine hydroxylation and subsequent cross-linking) in collagen matrix formation and mineralization in bone. ..
- Pornprasertsuk S, Duarte W, Mochida Y, Yamauchi M. Lysyl hydroxylase-2b directs collagen cross-linking pathways in MC3T3-E1 cells. J Bone Miner Res. 2004;19:1349-55 pubmed..3 mol/mol of collagen) in AS clones. The data clearly show a critical role of LH2b in determining collagen cross-linking pathways, most likely through its action on telopeptidyl Lys residues. ..
- Walker L, Teebi A, Marini J, De Paepe A, Malfait F, Atsawasuwan P, et al. 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. Mol Genet Metab. 2004;83:312-21 pubmed..These results suggest that the deficiency of LH2 in these fibroblasts may be caused by changes in other factors required for the expression of LH2. ..
- Kellokumpu S, Sormunen R, Heikkinen J, Myllyla R. Lysyl hydroxylase, a collagen processing enzyme, exemplifies a novel class of luminally-oriented peripheral membrane proteins in the endoplasmic reticulum. J Biol Chem. 1994;269:30524-9 pubmed..The results suggest a novel possibility by which ER lumen can acquire its specific protein components from the bulk flow. ..
- Giunta C, Randolph A, Al Gazali L, Brunner H, Kraenzlin M, Steinmann B. Nevo syndrome is allelic to the kyphoscoliotic type of the Ehlers-Danlos syndrome (EDS VIA). Am J Med Genet A. 2005;133A:158-64 pubmed
- Spotila L, Rodriguez H, Koch M, Tenenhouse H, Tenenhouse A, Li H, et al. Association analysis of bone mineral density and single nucleotide polymorphisms in two candidate genes on chromosome 1p36. Calcif Tissue Int. 2003;73:140-6 pubmed..04). These findings strengthen the potential importance of chromosome 1p36.2-1p36.3 in contributing to BMD variation, and are consistent with genetic variation in either PLOD1, TNFRSF1B or nearby genes playing a role in the phenotype. ..
- Saito M, Soshi S, Fujii K. Effect of hyper- and microgravity on collagen post-translational controls of MC3T3-E1 osteoblasts. J Bone Miner Res. 2003;18:1695-705 pubmed..These observations may be important in elucidating the mechanisms of osteopenia during space flight. ..
- Zuurmond A, van der Slot Verhoeven A, van Dura E, de Groot J, Bank R. Minoxidil exerts different inhibitory effects on gene expression of lysyl hydroxylase 1, 2, and 3: implications for collagen cross-linking and treatment of fibrosis. Matrix Biol. 2005;24:261-70 pubmed..We conclude that minoxidil is unlikely to serve as an anti-fibroticum, but confers features to the collagen matrix, which provide insight into the substrate specificity of LH1. ..
- Hjalt T, Amendt B, Murray J. PITX2 regulates procollagen lysyl hydroxylase (PLOD) gene expression: implications for the pathology of Rieger syndrome. J Cell Biol. 2001;152:545-52 pubmed..Mutations and rearrangements in PLOD-1 are known to be prevalent in patients with Ehlers-Danlos syndrome, kyphoscoliosis type (type VI [EDVI]). Several of the same organ systems are involved in Rieger syndrome and EDVI. ..
- Yis U, Dirik E, Chambaz C, Steinmann B, Giunta C. Differential diagnosis of muscular hypotonia in infants: the kyphoscoliotic type of Ehlers-Danlos syndrome (EDS VI). Neuromuscul Disord. 2008;18:210-4 pubmed..We advocate the analysis of urinary pyridinolines in all infants with severe hypotonia which is highly specific and sensitive, quick and inexpensive...
- Norman K, Moerman D. The let-268 locus of Caenorhabditis elegans encodes a procollagen lysyl hydroxylase that is essential for type IV collagen secretion. Dev Biol. 2000;227:690-705 pubmed..These observations indicate that type IV collagen is required in the basement membrane for mechanical support and not for organogenesis of the body wall muscle. ..
- van der Slot A, van Dura E, de Wit E, de Groot J, Huizinga T, Bank R, et al. Elevated formation of pyridinoline cross-links by profibrotic cytokines is associated with enhanced lysyl hydroxylase 2b levels. Biochim Biophys Acta. 2005;1741:95-102 pubmed..e., up-regulation of LH2b mRNA levels and increased formation of pyridinoline cross-links, previously recognized to be inherent to fibrotic processes, are induced by various profibrotic cytokines. ..
- Vangimalla S, Ganesan M, Kharbanda K, Osna N. Bifunctional Enzyme JMJD6 Contributes to Multiple Disease Pathogenesis: New Twist on the Old Story. Biomolecules. 2017;7: pubmed publisher..This article reviews the association of JMJD6 with various pathological processes-particularly, its role in tumorigenesis and virological interactions. ..
- Walker L, Overstreet M, Siddiqui A, De Paepe A, Ceylaner G, Malfait F, et al. A novel mutation in the lysyl hydroxylase 1 gene causes decreased lysyl hydroxylase activity in an Ehlers-Danlos VIA patient. J Invest Dermatol. 2005;124:914-8 pubmed..Although not in the major catalytic site, this mutation occurs in a highly conserved region of the LH1 gene and may contribute to loss of activity by interfering with normal folding of the enzyme. ..
- Gjaltema R, de Rond S, Rots M, Bank R. Procollagen Lysyl Hydroxylase 2 Expression Is Regulated by an Alternative Downstream Transforming Growth Factor Î²-1 Activation Mechanism. J Biol Chem. 2015;290:28465-76 pubmed publisher..This also suggests that additional activation strategies are used downstream of the TGFÎ²1 pathway, and hence their unraveling could be of great importance to fully understand TGFÎ²1 activation of genes. ..
- van der Slot A, Zuurmond A, van den Bogaerdt A, Ulrich M, Middelkoop E, Boers W, et al. Increased formation of pyridinoline cross-links due to higher telopeptide lysyl hydroxylase levels is a general fibrotic phenomenon. Matrix Biol. 2004;23:251-7 pubmed..We conclude that the increased expression of LH2b, leading to the increased formation of pyridinoline cross-links, is present in a wide variety of fibrotic disorders and thus represents a general fibrotic phenomenon. ..
- Salo A, Cox H, Farndon P, Moss C, Grindulis H, Risteli M, et al. A connective tissue disorder caused by mutations of the lysyl hydroxylase 3 gene. Am J Hum Genet. 2008;83:495-503 pubmed publisher..The disorder has a unique phenotype causing severe morbidity as a result of features that overlap with a number of known collagen disorders. ..
- Yeowell H, Walker L, Farmer B, Heikkinen J, Myllyla R. Mutational analysis of the lysyl hydroxylase 1 gene (PLOD) in six unrelated patients with Ehlers-Danlos syndrome type VI: prenatal exclusion of this disorder in one family. Hum Mutat. 2000;16:90 pubmed..Genotype analysis indicated that the Y511X mutation may originate from a common ancestral gene. Several alternative splicing pathways have been identified which bypass the PTCs and can also restore the open reading frame. ..
- Risteli M, Niemitalo O, Lankinen H, Juffer A, Myllyla R. Characterization of collagenous peptides bound to lysyl hydroxylase isoforms. J Biol Chem. 2004;279:37535-43 pubmed..The data do not indicate strict sequence specificity for the LH isoforms, but the data indicated that there was a clear preference for some sequences to be bound and hydroxylated by a certain isoform. ..
- Banushi B, Forneris F, Straatman Iwanowska A, Strange A, Lyne A, Rogerson C, et al. Regulation of post-Golgi LH3 trafficking is essential for collagen homeostasis. Nat Commun. 2016;7:12111 pubmed publisher..Thus, regulation of post-Golgi LH3 trafficking is essential for collagen homeostasis and for the development and function of multiple organs and tissues. ..
- Kaku M, Mochida Y, Atsawasuwan P, Parisuthiman D, Yamauchi M. Post-translational modifications of collagen upon BMP-induced osteoblast differentiation. Biochem Biophys Res Commun. 2007;359:463-8 pubmed..The results indicate that LHs and LOX/LOXLs are differentially responsive to BMP-induced osteoblast differentiation that may eventually lead to the specific collagen cross-linking pattern seen in bone. ..
- Bock O, Höftmann J, Theophile K, Hussein K, Wiese B, Schlue J, et al. Bone morphogenetic proteins are overexpressed in the bone marrow of primary myelofibrosis and are apparently induced by fibrogenic cytokines. Am J Pathol. 2008;172:951-60 pubmed publisher..We conclude that BMP family members may play an important role in the pathogenesis of myelofibrosis in PMF and are apparently induced by cytokines such as TGFbeta-1. ..
- Rautavuoma K, Takaluoma K, Passoja K, Pirskanen A, Kvist A, Kivirikko K, et al. 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. J Biol Chem. 2002;277:23084-91 pubmed..It is thus evident that human tissues must have additional glycosyltransferases that are responsible for most of the collagen glycosylation in vivo. ..
- Wang C, Risteli M, Heikkinen J, Hussa A, Uitto L, Myllyla R. Identification of amino acids important for the catalytic activity of the collagen glucosyltransferase associated with the multifunctional lysyl hydroxylase 3 (LH3). J Biol Chem. 2002;277:18568-73 pubmed..These data provide the information needed to design knock-out studies for investigation of the function of glucosylgalactosyl hydroxylysyl residues of collagens in vivo. ..
- Parikh F, Sivaramakrishnan A, Pai Dhungat J. Type VI Ehler Danlos Syndrome. J Assoc Physicians India. 2004;52:631 pubmed
- Ruotsalainen H, Sipilä L, Vapola M, Sormunen R, Salo A, Uitto L, et al. Glycosylation catalyzed by lysyl hydroxylase 3 is essential for basement membranes. J Cell Sci. 2006;119:625-35 pubmed..Together our results demonstrate for the first time the importance of hydroxylysine-linked glycosylation for collagens. ..
- Panková D, Chen Y, Terajima M, Schliekelman M, Baird B, Fahrenholtz M, et al. Cancer-Associated Fibroblasts Induce a Collagen Cross-link Switch in Tumor Stroma. Mol Cancer Res. 2016;14:287-95 pubmed publisher..CAFs induce a collagen cross-link switch in tumor stroma to influence the invasive properties of tumor cells. ..
- Hautala T, Heikkinen J, Kivirikko K, Myllyla R. A large duplication in the gene for lysyl hydroxylase accounts for the type VI variant of Ehlers-Danlos syndrome in two siblings. Genomics. 1993;15:399-404 pubmed..From Southern blotting data, the duplicated area in the gene equals about 6-9 kb and corresponds to seven exons. ..
- Yamada Y, Ando F, Shimokata H. Association of candidate gene polymorphisms with bone mineral density in community-dwelling Japanese women and men. Int J Mol Med. 2007;19:791-801 pubmed..The polymorphisms of ICAM1 and CNR2 may confer susceptibility to postmenopausal osteoporosis in women, and that of GJA4 to osteoporosis in men. ..
- Heard M, Besio R, Weis M, Rai J, Hudson D, Dimori M, et al. Sc65-Null Mice Provide Evidence for a Novel Endoplasmic Reticulum Complex Regulating Collagen Lysyl Hydroxylation. PLoS Genet. 2016;12:e1006002 pubmed publisher..This is the first indication of a prolyl-hydroxylase complex in the ER controlling lysyl-hydroxylase activity during collagen synthesis. ..
- Stein H, Wilensky M, Tsafrir Y, Rosenthal M, Amir R, Avraham T, et al. Production of bioactive, post-translationally modified, heterotrimeric, human recombinant type-I collagen in transgenic tobacco. Biomacromolecules. 2009;10:2640-5 pubmed publisher..Through a simple, safe and scalable method of rhCOL1 production and purification from tobacco plants, this work broadens the potential applications of human recombinant collagen in regenerative medicine. ..
- Ishida I, Saika S, Ohnishi Y. Effect of minoxidil on rabbit lens epithelial cell behavior in vitro and in situ. Graefes Arch Clin Exp Ophthalmol. 2001;239:770-7 pubmed..Minoxidil also attenuated repopulation of LECs on the inner surface of organ-cultured capsules. Minoxidil may be a potential inhibitor of postoperative capsular opacification. ..
- Hautala T, Byers M, Eddy R, Shows T, Kivirikko K, Myllyla R. Cloning of human lysyl hydroxylase: complete cDNA-derived amino acid sequence and assignment of the gene (PLOD) to chromosome 1p36.3----p36.2. Genomics. 1992;13:62-9 pubmed..2----1p36.3. This gene is thus not physically linked to those for the alpha and beta subunits of prolyl 4-hydroxylase, which are located on chromosomes 10 and 17, respectively. ..
- Passoja K, Rautavuoma K, Ala Kokko L, Kosonen T, Kivirikko K. Cloning and characterization of a third human lysyl hydroxylase isoform. Proc Natl Acad Sci U S A. 1998;95:10482-6 pubmed
- Bank R, Robins S, Wijmenga C, Breslau Siderius L, Bardoel A, van der Sluijs H, et al. Defective collagen crosslinking in bone, but not in ligament or cartilage, in Bruck syndrome: indications for a bone-specific telopeptide lysyl hydroxylase on chromosome 17. Proc Natl Acad Sci U S A. 1999;96:1054-8 pubmed..Further knowledge of this enzyme has important implications for conditions where aberrant expression of telopeptide lysyl hydroxylase occurs, such as fibrosis and scar formation. ..
- Schneider V, Granato M. The myotomal diwanka (lh3) glycosyltransferase and type XVIII collagen are critical for motor growth cone migration. Neuron. 2006;50:683-95 pubmed..Together, our results provide the first genetic evidence that glycosyltransferase modifications of the ECM play a critical role during vertebrate motor axon migration. ..
- Heikkinen J, Risteli M, Wang C, Latvala J, Rossi M, Valtavaara M, et al. Lysyl hydroxylase 3 is a multifunctional protein possessing collagen glucosyltransferase activity. J Biol Chem. 2000;275:36158-63 pubmed..In vitro mutagenesis experiments demonstrate that the amino acids involved in the GGT active site differ from those required for LH3 activity. ..
- Knippenberg M, Helder M, Doulabi B, Bank R, Wuisman P, Klein Nulend J. Differential effects of bone morphogenetic protein-2 and transforming growth factor-beta1 on gene expression of collagen-modifying enzymes in human adipose tissue-derived mesenchymal stem cells. Tissue Eng Part A. 2009;15:2213-25 pubmed publisher..AT-MSCs may thus be able to appropriately modify type I collagen to form a functional bone extracellular matrix for tissue engineering, dependent on the growth factor added. ..
- Mercer D, Nicol P, Kimbembe C, Robins S. Identification, expression, and tissue distribution of the three rat lysyl hydroxylase isoforms. Biochem Biophys Res Commun. 2003;307:803-9 pubmed..LH1 and LH2a expression and production led to an increase in total pyridinium cross-link production. Evidence that LH2a possesses telopeptide lysyl hydroxylase activity, previously thought to be a novel enzyme, is presented. ..
- Sipilä L, Szatanik M, Vainionpää H, Ruotsalainen H, Myllyla R, Guenet J. The genes encoding mouse lysyl hydroxylase isoforms map to chromosomes 4,5, and 9. Mamm Genome. 2000;11:1132-4 pubmed