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Amino Acid Metabolism and Regulation in Health and Disease

A special issue of International Journal of Molecular Sciences (ISSN 1422-0067). This special issue belongs to the section "Bioactives and Nutraceuticals".

Deadline for manuscript submissions: closed (31 December 2019) | Viewed by 39337

Special Issue Editors


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Guest Editor
Laboratory of Health Chemistry, Showa Pharmaceutical University, Machida, Tokyo 194-8543, Japan
Interests: amino acid metabolism; homocysteine; hydrogen sulfide; lysophospholipid signaling; proteomics; metabolomics; signal transduction
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E-Mail Website
Guest Editor
Department of Pathology and Biomedical Science, University of Otago, Christchurch, 2 Riccarton Avenue, P.O. Box 4345, Christchurch 8140, New Zealand
Interests: inflammation; acute pancreatitis; sepsis; burn injury; arthritis; hydrogen sulfide; substance P; chemokines; leukocytes
Special Issues, Collections and Topics in MDPI journals

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Guest Editor
Department of Microbiology, Biochemistry and Molecular Genetics, Rutgers New Jersey Medical School, Newark, NJ 07103, USA
Interests: genetic code; protein biosynthesis; tRNA synthetase; error-editing mechanisms; prebiotic chemistry; evolution of life; sulfur metabolism; homocysteine; protein modification; mTOR/autophagy; cardiovascular disease; Alzheimer's disease
Special Issues, Collections and Topics in MDPI journals

Special Issue Information

Dear Colleagues,

Amino acids, the primary component of proteins, are not stored in the human body, unlike carbohydrates and fats. The (free) amino acid pool is estimated to be only ~100 g in comparison with the amount of proteins (~12 kg) in a 70 kg person. Therefore, amino acids must be obtained from the diet, synthesized de novo (as are the eleven non-essential amino acids), or supplied from endogenous protein degradation. Amino acids can then be used for protein synthesis, the conversion to various nitrogen-containing essential biomolecules including neurotransmitters, purines and pyrimidines, porphyrins, creatine, and gaseous transmitters (NO, CO, and H2S), as well as an energy source. Six decades have passed since the identification of inborn errors in amino acid metabolism such as phenylketonuria, maple syrup disease, and homocystinuria. Thereafter, a growing body of evidence is accumulating to show the involvement of dysregulated amino acid metabolism in various aspects of common acquired disease conditions such as cardiovascular diseases, oncogenesis/tumor progression/metastasis, inflammation/autoimmune diseases, and metabolic syndrome. The Special Issue, “Amino Acid Metabolism and Regulation in Health and Disease”, of the International Journal of Molecular Sciences will include a selection of original research papers and reviews on the molecular and cellular biology of amino acids, including recently discovered fundamental aspects of regulation by bioactive amino acids (mTOR signaling and autophagy, sensing of amino acids by aminoacyl-tRNA synthetases), their metabolites (NO, H2S, homocysteine, and glutathione), and post-translational protein modification (S-nitrosylation, S-sulfhydration, S-glutathionylation, S- and N-homocysteinylation, and lysine residue aminoacylation), and their roles in health and disease.

Prof. Dr. Isao Ishii
Prof. Dr. Madhav Bhatia
Prof. Dr. Hieronim Jakubowski
Guest Editors

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Keywords

  • amino acids
  • amino acid derivatives
  • metabolism
  • aminoacyl-tRNA synthetases
  • protein modification
  • autophagy
  • mTOR signaling

Published Papers (9 papers)

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Research

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15 pages, 2332 KiB  
Article
A Simplified Method for Simultaneous Determination of α-Lipoic Acid and Low-Molecular-Mass Thiols in Human Plasma
by Kamila Borowczyk, Patrycja Olejarz, Grażyna Chwatko, Marcin Szylberg and Rafał Głowacki
Int. J. Mol. Sci. 2020, 21(3), 1049; https://doi.org/10.3390/ijms21031049 - 5 Feb 2020
Cited by 13 | Viewed by 3375
Abstract
α-Lipoic acid, glutathione, cysteine, and cysteinylglycine can be applied as therapeutic agents in civilization diseases such as diabetes mellitus, cardiovascular diseases, and cancers. On the other hand, a higher concentration of homocysteine can result in health problems and has been indicated as an [...] Read more.
α-Lipoic acid, glutathione, cysteine, and cysteinylglycine can be applied as therapeutic agents in civilization diseases such as diabetes mellitus, cardiovascular diseases, and cancers. On the other hand, a higher concentration of homocysteine can result in health problems and has been indicated as an independent risk factor for cardiovascular disease and accelerated atherosclerosis. Here, the first simplified HPLC-UV assay that enables simultaneous determination of α-lipoic acid and low-molecular-mass thiols in plasma, reduces the number of steps, shortens the total time of sample preparation, and limits the amount of single-use polypropylene laboratory materials is described. The assay is based on reversed-phase high performance liquid chromatography with UV detection and simultaneous reduction of disulfide bound with tris(2-carboxyethyl)phosphine and the selective pre-column derivatization of the thiol group with 1-benzyl-2-chloropyridinium bromide. Linearity in the detector responses for plasma samples were observed in ranges: 0.12–5.0 nmol mL−1 for α-lipoic acid; 2.0–20.0 nmol mL−1 for glutathione, cysteinylglycine, and homocysteine; and 40.0–400.0 for cysteine. The LODs for α-lipoic acid and low-molecular-mass thiols were 0.08 and 0.12 nmol mL−1, respectively, while LOQs were 0.12 and 0.16 nmol mL−1, respectively. The usefulness of the proposed method has been proven by its application to real samples. Full article
(This article belongs to the Special Issue Amino Acid Metabolism and Regulation in Health and Disease)
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18 pages, 1974 KiB  
Article
Increased Urinary 3-Mercaptolactate Excretion and Enhanced Passive Systemic Anaphylaxis in Mice Lacking Mercaptopyruvate Sulfurtransferase, a Model of Mercaptolactate-Cysteine Disulfiduria
by Noriyuki Akahoshi, Tatsuro Minakawa, Masashi Miyashita, Uran Sugiyama, Chihiro Saito, Rintaro Takemoto, Akihiro Honda, Waka Kamichatani, Shotaro Kamata, Yasumi Anan and Isao Ishii
Int. J. Mol. Sci. 2020, 21(3), 818; https://doi.org/10.3390/ijms21030818 - 27 Jan 2020
Cited by 14 | Viewed by 3522
Abstract
Mercaptopyruvate sulfurtransferase (Mpst) and its homolog thiosulfate sulfurtransferase (Tst = rhodanese) detoxify cyanide to thiocyanate. Mpst is attracting attention as one of the four endogenous hydrogen sulfide (H2S)/reactive sulfur species (RSS)-producing enzymes, along with cystathionine β-synthase (Cbs), cystathionine γ-lyase (Cth), and [...] Read more.
Mercaptopyruvate sulfurtransferase (Mpst) and its homolog thiosulfate sulfurtransferase (Tst = rhodanese) detoxify cyanide to thiocyanate. Mpst is attracting attention as one of the four endogenous hydrogen sulfide (H2S)/reactive sulfur species (RSS)-producing enzymes, along with cystathionine β-synthase (Cbs), cystathionine γ-lyase (Cth), and cysteinyl-tRNA synthetase 2 (Cars2). MPST deficiency was found in 1960s among rare hereditary mercaptolactate-cysteine disulfiduria patients. Mpst-knockout (KO) mice with enhanced liver Tst expression were recently generated as its model; however, the physiological roles/significances of Mpst remain largely unknown. Here we generated three independent germ lines of Mpst-KO mice by CRISPR/Cas9 technology, all of which maintained normal hepatic Tst expression/activity. Mpst/Cth-double knockout (DKO) mice were generated via crossbreeding with our previously generated Cth-KO mice. Mpst-KO mice were born at the expected frequency and developed normally like Cth-KO mice, but displayed increased urinary 3-mercaptolactate excretion and enhanced passive systemic anaphylactic responses when compared to wild-type or Cth-KO mice. Mpst/Cth-DKO mice were also born at the expected frequency and developed normally, but excreted slightly more 3-mercaptolactate in urine compared to Mpst-KO or Cth-KO mice. Our Mpst-KO, Cth-KO, and Mpst/Cth-DKO mice, unlike semi-lethal Cbs-KO mice and lethal Cars2-KO mice, are useful tools for analyzing the unknown physiological roles of endogenous H2S/RSS production. Full article
(This article belongs to the Special Issue Amino Acid Metabolism and Regulation in Health and Disease)
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15 pages, 4078 KiB  
Article
Effect of Glycine on BV-2 Microglial Cells Treated with Interferon-γ and Lipopolysaccharide
by Florentina Egger, Martin Jakab, Julia Fuchs, Karin Oberascher, Gabriele Brachtl, Markus Ritter, Hubert H. Kerschbaum and Martin Gaisberger
Int. J. Mol. Sci. 2020, 21(3), 804; https://doi.org/10.3390/ijms21030804 - 26 Jan 2020
Cited by 11 | Viewed by 4015
Abstract
Microglia are first-line defense antigen-presenting phagocytes in the central nervous system. Activated microglial cells release pro-inflammatory cytokines and can trigger an oxidative burst. The amino acid glycine exerts anti-inflammatory, immunomodulatory and cytoprotective effects and influences cell volume regulation. This study aimed to investigate [...] Read more.
Microglia are first-line defense antigen-presenting phagocytes in the central nervous system. Activated microglial cells release pro-inflammatory cytokines and can trigger an oxidative burst. The amino acid glycine exerts anti-inflammatory, immunomodulatory and cytoprotective effects and influences cell volume regulation. This study aimed to investigate the role of glycine in the modulation of inflammatory processes in mouse BV-2 microglial cells. Inflammatory stress was induced by lipopolysaccharide/interferon-γ (LPS/IFN-γ) treatment for 24 h in the absence or presence of 1 or 5 mM glycine. Cells were analyzed by flow cytometry for cell volume, side scatter, apoptosis/necrosis and expression of activation-specific surface markers. Apoptosis progression was monitored by life cell imaging. Reduced glutathione/oxidized glutathione (GSH/GSSG) ratios and release of the pro-inflammatory cytokines IL-6 and TNF-α were measured using luminescence-based assays and ELISA, respectively. We found that LPS/IFN-γ-induced apoptosis was decreased and the fraction of living cells was increased by glycine. Expression of the surface markers CD11b, CD54 and CD80 was dose-dependently increased, while IL-6 and TNF-α release was not altered compared to LPS/IFN-γ-treated cells. We showed that in BV-2 microglial cells glycine improves viability and counteracts deleterious responses to LPS/IFN-γ, which might be relevant in neurodegenerative processes associated with inflammation, like Alzheimer’s or Parkinson’s disease. Full article
(This article belongs to the Special Issue Amino Acid Metabolism and Regulation in Health and Disease)
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16 pages, 4274 KiB  
Article
Effect of Methionine Diet on Metabolic and Histopathological Changes of Rat Hippocampus
by Maria Kovalska, Petra Hnilicova, Dagmar Kalenska, Barbara Tothova, Marian Adamkov and Jan Lehotsky
Int. J. Mol. Sci. 2019, 20(24), 6234; https://doi.org/10.3390/ijms20246234 - 10 Dec 2019
Cited by 12 | Viewed by 2852
Abstract
Hyperhomocysteinemia (hHcy) is regarded as an independent and strong risk factor for cerebrovascular diseases, stroke, and dementias. The hippocampus has a crucial role in spatial navigation and memory processes and is being constantly studied for neurodegenerative disorders. We used a moderate methionine (Met) [...] Read more.
Hyperhomocysteinemia (hHcy) is regarded as an independent and strong risk factor for cerebrovascular diseases, stroke, and dementias. The hippocampus has a crucial role in spatial navigation and memory processes and is being constantly studied for neurodegenerative disorders. We used a moderate methionine (Met) diet at a dose of 2 g/kg of animal weight/day in duration of four weeks to induce mild hHcy in adult male Wistar rats. A novel approach has been used to explore the hippocampal metabolic changes using proton magnetic resonance spectroscopy (1H MRS), involving a 7T MR scanner in combination with histochemical and immunofluorescence analysis. We found alterations in the metabolic profile, as well as remarkable histo-morphological changes such as an increase of hippocampal volume, alterations in number and morphology of astrocytes, neurons, and their processes in the selective vulnerable brain area of animals treated with a Met-enriched diet. Results of both methodologies suggest that the mild hHcy induced by Met-enriched diet alters volume, histo-morphological pattern, and metabolic profile of hippocampal brain area, which might eventually endorse the neurodegenerative processes. Full article
(This article belongs to the Special Issue Amino Acid Metabolism and Regulation in Health and Disease)
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17 pages, 1551 KiB  
Article
Application of Butylamine as a Conjugative Reagent to On-Column Derivatization for the Determination of Antioxidant Amino Acids in Brain Tissue, Plasma, and Urine Samples
by Kamila Borowczyk, Patrycja Olejarz, Adrianna Kamińska, Rafał Głowacki and Grażyna Chwatko
Int. J. Mol. Sci. 2019, 20(13), 3340; https://doi.org/10.3390/ijms20133340 - 7 Jul 2019
Cited by 2 | Viewed by 2651
Abstract
(1) Antioxidants are involved in body protection mechanisms against reactive oxygen species. Amino acids such as glutathione (GSH) and N-acetylcysteine (NAC) are known to be involved in providing protection against oxidative lethality. A quick and simple method for the determination of NAC [...] Read more.
(1) Antioxidants are involved in body protection mechanisms against reactive oxygen species. Amino acids such as glutathione (GSH) and N-acetylcysteine (NAC) are known to be involved in providing protection against oxidative lethality. A quick and simple method for the determination of NAC and GSH in various biological matrices such as urine, plasma, and homogenates of brain tissues has been developed and described in this work. (2) The assay is based on reversed phase high performance liquid chromatography with spectrofluorimetric detection and on-column derivatization. Butylamine and o-phthaldialdehyde have been used as derivatization reagents. Since o-phthaldialdehyde constitutes a part of the mobile phase, the derivatization reaction and chromatographic separation occur simultaneously. (3) Linearity in the detector response for NAC in human urine was observed in the range of 5–200 nmol mL−1, and NAC and GSH in the brain tissue homogenates were observed in the range of 0.5–5 nmol mL−1 and 0.5–15 nmol mL−1, respectively. Human plasma linearity ranges covered 0.25–5.00 nmol mL−1 and 0.5–15 nmol mL−1 for NAC and GSH, respectively. The LODs for NAC and GSH were 0.01 and 0.02 nmol mL−1 while the LOQs were 0.02 and 0.05 nmol mL−1, respectively. The usefulness of the proposed method was proven through its application to real samples. Full article
(This article belongs to the Special Issue Amino Acid Metabolism and Regulation in Health and Disease)
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9 pages, 1956 KiB  
Article
Cystathionine-Gamma-Lyase-Derived Hydrogen Sulfide-Regulated Substance P Modulates Liver Sieve Fenestrations in Caecal Ligation and Puncture-Induced Sepsis
by Ravinder R Gaddam, Stephen Chambers, Robin Fraser, Victoria C Cogger, David G Le Couteur, Isao Ishii and Madhav Bhatia
Int. J. Mol. Sci. 2019, 20(13), 3191; https://doi.org/10.3390/ijms20133191 - 29 Jun 2019
Cited by 12 | Viewed by 3612
Abstract
Cystathionine-γ-lyase (CSE) is a hydrogen sulfide (H2S)-synthesizing enzyme that promotes inflammation by upregulating H2S in sepsis. Liver sinusoidal endothelial cells (LSECs) are fenestrated endothelial cells (liver sieve) that undergo alteration during sepsis and H2S plays a role [...] Read more.
Cystathionine-γ-lyase (CSE) is a hydrogen sulfide (H2S)-synthesizing enzyme that promotes inflammation by upregulating H2S in sepsis. Liver sinusoidal endothelial cells (LSECs) are fenestrated endothelial cells (liver sieve) that undergo alteration during sepsis and H2S plays a role in this process. Substance P (SP) is encoded by the preprotachykinin A (PPTA) gene, and promotes inflammation in sepsis; however, its regulation by H2S is poorly understood. Furthermore, the interaction between H2S and SP in modulating LSEC fenestrations following sepsis remains unclear. This study aimed to investigate whether CSE/H2S regulates SP and the neurokinin-1 receptor (NK-1R) and modulates fenestrations in LSECs following caecal ligation and puncture (CLP)-induced sepsis. Here we report that the absence of either CSE or H2S protects against liver sieve defenestration and gaps formation in LSECs in sepsis by decreased SP-NK-1R signaling. Following sepsis, there is an increased expression of liver CSE and H2S synthesis, and plasma H2S levels, which were aligned with higher SP levels in the liver, lungs and plasma and NK-1R in the liver and lungs. The genetic deletion of CSE led to decreased sepsis-induced SP and NK-1R in the liver, lungs and plasma SP suggesting H2S synthesized through CSE regulates the SP-NK-1R pathway in sepsis. Further, mice deficient in the SP-encoding gene (PPTA) preserved sepsis-induced LSEC defenestration and gaps formation, as seen by maintenance of patent fenestrations and fewer gaps. In conclusion, CSE/H2S regulates SP-NK-1R and modulates LSEC fenestrations in sepsis. Full article
(This article belongs to the Special Issue Amino Acid Metabolism and Regulation in Health and Disease)
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20 pages, 1312 KiB  
Article
Serum Proteome Alterations in Human Cystathionine β-Synthase Deficiency and Ischemic Stroke Subtypes
by Marta Sikora, Izabela Lewandowska, Małgorzata Kupc, Jolanta Kubalska, Ałła Graban, Łukasz Marczak, Radosław Kaźmierski and Hieronim Jakubowski
Int. J. Mol. Sci. 2019, 20(12), 3096; https://doi.org/10.3390/ijms20123096 - 25 Jun 2019
Cited by 11 | Viewed by 3984
Abstract
Ischemic stroke induces brain injury via thrombotic or embolic mechanisms involving large or small vessels. Cystathionine β-synthase deficiency (CBS), an inborn error of metabolism, is associated with vascular thromboembolism, the major cause of morbidity and mortality in affected patients. Because thromboembolism involves the [...] Read more.
Ischemic stroke induces brain injury via thrombotic or embolic mechanisms involving large or small vessels. Cystathionine β-synthase deficiency (CBS), an inborn error of metabolism, is associated with vascular thromboembolism, the major cause of morbidity and mortality in affected patients. Because thromboembolism involves the brain vasculature in these patients, we hypothesize that CBS deficiency and ischemic stroke have similar molecular phenotypes. We used label-free mass spectrometry for quantification of changes in serum proteomes in CBS-deficient patients (n = 10) and gender/age-matched unaffected controls (n = 14), as well as in patients with cardioembolic (n = 17), large-vessel (n = 26), or lacunar (n = 25) ischemic stroke subtype. In CBS-deficient patients, 40 differentially expressed serum proteins were identified, of which 18 were associated with elevated homocysteine (Hcy) and 22 were Hcy-independent. We also identified Hcy-independent differentially expressed serum proteins in ischemic stroke patients, some of which were unique to a specific subtype: 10 of 32 for cardioembolic vs. large-vessel, six of 33 for cardioembolic vs. lacunar, and six of 23 for large-vessel vs. lacunar. There were significant overlaps between proteins affected by CBS deficiency and ischemic stroke, particularly the cardioembolic subtype, similar to protein overlaps between ischemic stroke subtypes. Top molecular pathways affected by CBS deficiency and ischemic stroke subtypes included acute phase response signaling and coagulation system. Similar molecular networks centering on NFκB were affected by CBS deficiency and stroke subtypes. These findings suggest common mechanisms involved in the pathologies of CBS deficiency and ischemic stroke subtypes. Full article
(This article belongs to the Special Issue Amino Acid Metabolism and Regulation in Health and Disease)
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9 pages, 412 KiB  
Article
Goeckerman Therapy of Psoriasis: Genotoxicity, Dietary Micronutrients, Homocysteine, and MTHFR Gene Polymorphisms
by Martin Beranek, Andrea Malkova, Zdenek Fiala, Jan Kremlacek, Kvetoslava Hamakova, Lenka Zaloudkova, Pavel Borsky, Tomas Adamus, Vladimir Palicka and Lenka Borska
Int. J. Mol. Sci. 2019, 20(8), 1908; https://doi.org/10.3390/ijms20081908 - 17 Apr 2019
Cited by 4 | Viewed by 3260
Abstract
Goeckerman therapy (GT) of psoriasis vulgaris is based on the application of crude coal tar and ultraviolet radiation. We investigated DNA damage by the number of micronucleated binucleated cells (MNBC) in lymphocytes, serum homocysteine, vitamin B12, folic acid, and two polymorphisms (C677T and [...] Read more.
Goeckerman therapy (GT) of psoriasis vulgaris is based on the application of crude coal tar and ultraviolet radiation. We investigated DNA damage by the number of micronucleated binucleated cells (MNBC) in lymphocytes, serum homocysteine, vitamin B12, folic acid, and two polymorphisms (C677T and A1298C) in the MTHFR gene in 35 patients with exacerbated psoriasis vulgaris classified according to the psoriasis area and severity index (PASI) score and treated by GT. The median of PASI score decreased from nineteen to five, and MNBC increased from 10 to 18‰ after GT (p < 0.001 in both cases). Correlations of MNBC with homocysteine (Spearman’s rho = 0.420, p = 0.012) and vitamin B12 (rho = −0.389, p = 0.021) before the therapy were observed. Hyperhomocysteinemia was an independent predictor of genotoxicity (OR 9.91; 95% CI, 2.09–55.67; p = 0.003). Homocysteine was higher in females than in males (13 vs. 12 µmol/L, p = 0.045). In contrast, vitamin B12 levels in the females were lower than in the males (160 vs. 192 pmol/L, p = 0.047). Vitamin B12 in the females were negatively influenced by smoking status (160 pmol/L in smokers vs. 192 pmol/L in non-smokers, p = 0.025). A significantly higher MNBC was found in CC homozygous patients (A1298C polymorphism) than in AC heterozygotes (32 vs. 16‰, p = 0.005) and AA homozygotes (32 vs. 18‰, p = 0.036). Our data showed that homocysteine participates in the pathogenesis of psoriasis. Its serum levels correlated with MNBC and allowed the prediction of DNA damage to appear within GT. Both micronutrients status and homocysteine metabolic pathway contribute to the genotoxicity of GT. Full article
(This article belongs to the Special Issue Amino Acid Metabolism and Regulation in Health and Disease)
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Review

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40 pages, 1075 KiB  
Review
Dysregulation of Epigenetic Mechanisms of Gene Expression in the Pathologies of Hyperhomocysteinemia
by Joanna Perła-Kaján and Hieronim Jakubowski
Int. J. Mol. Sci. 2019, 20(13), 3140; https://doi.org/10.3390/ijms20133140 - 27 Jun 2019
Cited by 60 | Viewed by 10502
Abstract
Hyperhomocysteinemia (HHcy) exerts a wide range of biological effects and is associated with a number of diseases, including cardiovascular disease, dementia, neural tube defects, and cancer. Although mechanisms of HHcy toxicity are not fully uncovered, there has been a significant progress in their [...] Read more.
Hyperhomocysteinemia (HHcy) exerts a wide range of biological effects and is associated with a number of diseases, including cardiovascular disease, dementia, neural tube defects, and cancer. Although mechanisms of HHcy toxicity are not fully uncovered, there has been a significant progress in their understanding. The picture emerging from the studies of homocysteine (Hcy) metabolism and pathophysiology is a complex one, as Hcy and its metabolites affect biomolecules and processes in a tissue- and sex-specific manner. Because of their connection to one carbon metabolism and editing mechanisms in protein biosynthesis, Hcy and its metabolites impair epigenetic control of gene expression mediated by DNA methylation, histone modifications, and non-coding RNA, which underlies the pathology of human disease. In this review we summarize the recent evidence showing that epigenetic dysregulation of gene expression, mediated by changes in DNA methylation and histone N-homocysteinylation, is a pathogenic consequence of HHcy in many human diseases. These findings provide new insights into the mechanisms of human disease induced by Hcy and its metabolites, and suggest therapeutic targets for the prevention and/or treatment. Full article
(This article belongs to the Special Issue Amino Acid Metabolism and Regulation in Health and Disease)
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