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

• The kyphoscoliotic type of Ehlers-Danlos syndrome (EDS type VIA) (OMIM 225400) is an autosomal recessive connective tissue disorder that results from mutations in the lysyl hydroxylase 1 gene (PLOD1) causing underhydroxylation of lysine residues in tissue collagens, particularly of skin [8].
• Deletion of cysteine 369 in lysyl hydroxylase 1 eliminates enzyme activity and causes Ehlers-Danlos syndrome type VI [9].
• Ehlers-Danlos syndrome in two siblings with deficient lysyl hydroxylase activity in cultured skin fibroblasts but only mild hydroxylysine deficit in skin [10].
• Biological function was tested by inserting portions of the 5'-flanking region of the gene next to the herpes simplex virus thymidine kinase promoter fused to the chloramphenicol acetyltransferase gene (LH beta-tkCAT) and performing gene transfer experiments with the pituitary GH3 cell line [11].
• They typically show Leydig cell hyperplasia and increased testosterone production typical for their age, whereas circulating LH concentrations remain prepubertal [12].

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

• In contrast to the effect of LH1 deficiency in EDS VI patients, the decreased expression of LH2 does not affect LH activity, bifunctional collagen cross-links (measured after reduction as dihydroxylysinonorleucine (DHLNL) and hydroxylysinonorleucine (HLNL)), or helical lysine hydroxylation in these cell lines [16].
• The kyphoscoliotic type of Ehlers-Danlos syndrome (EDS VIA) is an inheritable connective tissue disorder characterized by a deficiency of lysyl hydroxylase due to mutations in PLOD1 [1].
• Cloning, expression analysis, and ubiquitous overexpression of other LH family members reveals that only diwanka (lh3) possesses a critical role in growth cone migration [7].
• Cloning and characterization of a novel human lysyl hydroxylase isoform highly expressed in pancreas and muscle [17].
• A single C-terminal peptide segment mediates both membrane association and localization of lysyl hydroxylase in the endoplasmic reticulum [18].

Associations of PLOD1 with chemical compounds

• Lysyl hydroxylase (LH) catalyzes the formation of hydroxylysine in collagens; three human isoenzymes have been cloned so far [19].
• LH hydroxylates specific lysine residues in the collagen molecule that are precursors for the formation of cross-links which provide collagen with its tensile strength [16].
• Lysyl hydroxylase 2 contains nine cysteine residues, which are conserved in lysyl hydroxylase 1 [17].
• The increase in pyridinoline cross-links is likely to be the result of increased activity of the enzyme responsible for the hydroxylation of the telopeptides (telopeptide lysyl hydroxylase, or TLH) [3].
• Furthermore, the conserved histidines and aspartate residues required for lysyl hydroxylase activity are present in the sequence [17].

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

• The PLOD-1 promoter induces the expression of a luciferase reporter gene in the presence of PITX2 in cotransfection experiments [21].
• The mRNA for lysyl hydroxylase was reduced by one-third under the influence of TGF-beta 1 [22].

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 1.14.11.4), 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

• After the cloning of cDNAs and amplification by PCR, sequence analysis revealed two equally distributed populations of cDNAs for LH in the AT750 cell line [25].
• Activities of four intracellular enzymes of collagen biosynthesis--prolyl hydroxylase, lysyl hydroxylase, collagen galactosyltransferase, and collagen glucosyltransferase--were demonstrated in human platelets, and the presence of prolyl hydroxylase protein was further demonstrated by direct radioimmunoassay [26].
• Site-directed mutagenesis of human lysyl hydroxylase expressed in insect cells. Identification of histidine residues and an aspartic acid residue critical for catalytic activity [27].
• We have isolated a partial (2.2-kb) cDNA for LH from human skin fibroblasts using PCR [24].
• The LH cDNA hybridized strongly with two mRNA species of 2.4 and 3.4 kb on Northern blots of normal fibroblast RNA [24].

References