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Hyperornithinemia, hyperammonemia, homocitrullinuria syndrome
Published in William L. Nyhan, Georg F. Hoffmann, Aida I. Al-Aqeel, Bruce A. Barshop, Atlas of Inherited Metabolic Diseases, 2020
William L. Nyhan, Georg F. Hoffmann, Aida I. Al-Aqeel, Bruce A. Barshop
Homocitrullinuria is the third major feature of the disease. In the presence of accumulated carbamylphosphate, lysine is carboxylated to form homocitrulline (see Figure 31.1), which is efficiently excreted in the urine. Reported levels of excretion have ranged from 93 to 2380 μmol/g creatinine. As in the case of the orotic aciduria, homocitrullinuria may be absent or not prominent in patients receiving little protein in their diets. Its levels of excretion can be correlated with protein intake [26] or the administration of lysine, and good correlation was observed between the urinary homocitrulline: creatinine ratio and the plasma lysine: ornithine ratio [26]. Homocitrulline is commonly found in the urine of infants and children, a consequence of its formation by the heat treatment of milk products, and its subsequent ingestion and excretion [27, 28]. It is often found in patients with generalized aminoaciduria and regularly follows lysine loading in normal children and adults [29].
The Modification of Lysine
Published in Roger L. Lundblad, Chemical Reagents for Protein Modification, 2020
In an elegant study by Plapp and co-workers,61 the modification of lysyl residues in bovine pancreatic deoxyribonuclease A by several different reagents, including cyanate, was examined as shown in Figure 15. The modification with cyanate is performed at 37°C in 1.0 M triethanolamine hydrochloride, pH 8.0. The extent of modification was determined by analysis for homocitrulline following acid hydrolysis. A time course of hydrolysis was utilized to provide for the accurate determination of homocitrulline since this amino acid slowly decomposes to form lysine during acid hydrolysis (see above). This modification was sensitive to the conformation of the protein since both the extent of modification and loss of catalytic activity depended on the presence or absence of calcium ions as shown in Figures 16 and 17.
Potential interference of in vitro carbamylation on C-reactive protein laboratory measurement
Published in Scandinavian Journal of Clinical and Laboratory Investigation, 2023
Carolina dos Santos Stein, José Pedro Etchepare Cassol, Rafael Noal Moresco
In vitro carbamylation was induced using KOCN or urea. KOCN solutions were prepared in 0.1 mol/L phosphate-buffered saline (PBS; pH 7.4) to obtain final concentrations of 150 nM, 150 µM, and 150 mM. These experimental conditions were based on a previous study [15] that characterized the occurrence of carbamylation and the presence of homocitrulline. Urea solutions were tested at concentrations of 20, 100, and 500 mg/dL to reproduce a wide range of values associated with healthy and pathological conditions. After the addition of these solutions to a standard solution of CRP at a final concentration of 10 mg/L and a human serum pool spiked with the CRP standard solution, the samples were incubated at 37 °C for 24 h. All tests were conducted in replicates (n = 4). The serum pool was prepared from randomly selected samples of patients who had undergone routine laboratory tests at the University Hospital of Santa Maria, RS, Brazil. The study protocol was approved by the Institutional Ethics Committee (number 11559119.4.0000.5346). For the characterization of carbamylation, the standard solution of CRP at a final concentration of 10 mg/L was incubated at 37 °C for 24 h with PBS, KOCN, and urea at the highest concentrations, under conditions similar to those previously described. Assays were performed in triplicate. After incubation, the samples were dialyzed for 12 h in a dialysis tube containing a cellulose membrane (Membra-Cel® MD34, Sigma-Aldrich, St. Louis, MO, USA) against PBS to remove KOCN or urea excess.
Citrullinated and homocitrullinated low- density lipoprotein in rheumatoid arthritis
Published in Scandinavian Journal of Rheumatology, 2021
A Rajamohan, B Heit, E Cairns, L Barra
For both RA and CVD, post-translational modifications of proteins play an important role in pathogenic mechanisms. RA is characterized by the production of antibodies to proteins/peptides containing citrulline, a post-translational modification generated by deimination of arginine catalysed by peptidyl arginine deiminase (PAD). This enzyme is upregulated in inflammation. The current disease paradigm is that protein citrullination at mucosal sites, due to inflammation from infection and/or smoking in genetically susceptible individuals, leads to T- and B-cell responses to citrullinated proteins/peptides (7, 8). RA patients also have immune responses to homocitrullinated (otherwise known as carbamylated) proteins/peptides (9–11). Homocitrulline is a non-enzymic modification of lysine that occurs in the presence of cyanate, which is elevated in smoking and uraemia, producing a post-translational modification that is structurally similar to citrulline, differing by one additional carbon (12). Through epitope spreading, immune responses targeting proteins/peptides containing either of these modifications can occur at sites distal to the initial break in tolerance (8). Homocitrullinated proteins and immune complexes containing citrullinated proteins have been detected in the joints of RA patients (13, 14) and atherosclerotic plaque (12, 15).
Association of rheumatoid arthritis disease activity and antibodies to periodontal bacteria with serum lipoprotein profile in drug naive patients
Published in Annals of Medicine, 2020
Aulikki Kononoff, Pia Elfving, Pirkko Pussinen, Sohvi Hörkkö, Hannu Kautiainen, Leena Arstila, Leena Laasonen, Elina Savolainen, Helena Niinisalo, Jarno Rutanen, Olga Marjoniemi, Mari Hämäläinen, Katriina Vuolteenaho, Eeva Moilanen, Oili Kaipiainen-Seppänen
Carbamylation, a form of post-translational modification, can occur spontaneously or via a route assisted by myeloperoxidase [11]. Myeloperoxidase catalyses the oxidation of thiocyanate to cyanate. The active form of cyanate acts as a potential toxin and interacts with the amine groups of proteins generating homocitrulline [12]. Smoking elevates serum thiocyanate levels and may facilitate carbamylation by myeloperoxidase. The development of seropositive RA is associated with smoking [13]. As a proof of in vivo occurrence, immunoglobulin (Ig) G antibodies recognizing homocitrulline-containing antigens in serum, carbamylated Igs in synovial fluid and protein-bound homocitrulline in joint tissues have been described in RA (reviewed in [14]). Carbamylation also occurs in lipoprotein particles. Carbamylation of 15% of lysine residues completely abolished the interaction of LDL particle with its receptor [15]. Extensively carbamylated LDL is efficiently cleared from the circulation, whereas minimally carbamylated LDL has decreased clearance [16].