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Homocysteine in Protein Structure and Function and Human Disease
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Homocysteine in Protein Structure and Function and Human 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: 20 January 2025 | Viewed by 4084

Special Issue Editor

Prof. Dr. Hieronim Jakubowski

E-Mail Website
Guest Editor
Department of Microbiology, Biochemistry and Molecular Genetics, Rutgers New Jersey Medical School, Newark, NJ 07103, USA
Interests: Alzheimer's; autophagy; cardiovascular disease epigenetic regulation; error-editing mechanisms; evolution of peptide bond synthesis; gene expression; homocysteine; mTOR signalling neurological disease; protein modification; protein synthesis tRNA synthetase
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Special Issue Information

Dear Colleagues,

Homocysteine (Hcy) links two key metabolic pathways: the one-carbon/folate cycle, which provides one-carbon units for nucleotide and amino acid biosynthesis, and sulfur–amino acid metabolism, which regenerates methionine (Met) and provides cysteine (Cys). While Met and Cys are genetically encoded proteinogenic amino acids, Hcy is non-proteinogenic; however, although Hcy is not genetically encoded, proteins in our body have Hcy residues linked to lysine (Lys) residues via iso-peptide bonds (formed in a chemical reaction with Hcy-thiolactone, i.e., N-homocysteinylation) or to cysteine residues via disulfide bonds (S-homocysteinylation).

Proteins also contain Hcy bound by a peptide bond within the polypeptide chain. Such homocysteinylated proteins are formed either post-translationally via a copper/iron-dependent demethylation of Met residues or via a nitric-oxide-dependent translational mechanism on ribosomes, in which S-NO-Hcy substitutes for Met. Accumulating evidence suggests that N-Hcy-protein can promote cancer, diabetes, cardiovascular disease/stroke, neurodegenerative diseases, infertility, and pregnancy complications.

This Special Issue of the IJMS, entitled “Homocysteine in Protein Structure and Function and Human Disease”, will include a selection of original research papers and reviews on the molecular/cellular biology and pathophysiology of Hcy metabolites. Papers describing recent studies on N-Hcy-protein chemical biology and on the dysregulation of fundamental biological processes, such as mTOR signaling, autophagy, amyloid precursor protein processing, and others, due to N-Hcy-protein/Hcy-thiolactone/Hcy are welcomed.

Prof. Dr. Hieronim Jakubowski
Guest Editor

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Keywords

  • Alzheimer's disease
  • amyloid beta
  • autophagy
  • cardiovascular disease
  • epigenetic regulation
  • homocysteine thiolactone
  • methionyl-tRNA synthetase
  • mTOR signalling
  • protein homocysteinylation

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Published Papers (3 papers)

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Research

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17 pages, 7270 KiB  
Article
Effects of Aerobic Treadmill Training on Oxidative Stress Parameters, Metabolic Enzymes, and Histomorphometric Changes in Colon of Rats with Experimentally Induced Hyperhomocysteinemia
by Marija Stojanović, Dušan Todorović, Kristina Gopčević, Ana Medić, Milica Labudović Borović, Sanja Despotović and Dragan Djuric
Int. J. Mol. Sci. 2024, 25(4), 1946; https://doi.org/10.3390/ijms25041946 - 6 Feb 2024
Cited by 1 | Viewed by 1245
Abstract
The aim of this study was to investigate the effects of aerobic treadmill training regimen of four weeks duration on oxidative stress parameters, metabolic enzymes, and histomorphometric changes in the colon of hyperhomocysteinemic rats. Male Wistar albino rats were divided into four groups [...] Read more.
The aim of this study was to investigate the effects of aerobic treadmill training regimen of four weeks duration on oxidative stress parameters, metabolic enzymes, and histomorphometric changes in the colon of hyperhomocysteinemic rats. Male Wistar albino rats were divided into four groups (n = 10, per group): C, 0.9% NaCl 0.2 mL/day subcutaneous injection (s.c.) 2x/day; H, homocysteine 0.45 µmol/g b.w./day s.c. 2x/day; CPA, saline (0.9% NaCl 0.2 mL/day s.c. 2x/day) and an aerobic treadmill training program; and HPA, homocysteine (0.45 µmol/g b.w./day s.c. 2x/day) and an aerobic treadmill training program. The HPA group had an increased level of malondialdehyde (5.568 ± 0.872 μmol/mg protein, p = 0.0128 vs. CPA (3.080 ± 0.887 μmol/mg protein)), catalase activity (3.195 ± 0.533 U/mg protein, p < 0.0001 vs. C (1.467 ± 0.501 U/mg protein), p = 0.0012 vs. H (1.955 ± 0.293 U/mg protein), and p = 0.0003 vs. CPA (1.789 ± 0.256 U/mg protein)), and total superoxide dismutase activity (9.857 ± 1.566 U/mg protein, p < 0.0001 vs. C (6.738 ± 0.339 U/mg protein), p < 0.0001 vs. H (6.015 ± 0.424 U/mg protein), and p < 0.0001 vs. CPA (5.172 ± 0.284 U/mg protein)) were detected in the rat colon. In the HPA group, higher activities of lactate dehydrogenase (2.675 ± 1.364 mU/mg protein) were detected in comparison to the CPA group (1.198 ± 0.217 mU/mg protein, p = 0.0234) and higher activities of malate dehydrogenase (9.962 (5.752–10.220) mU/mg protein) were detected in comparison to the CPA group (4.727 (4.562–5.299) mU/mg protein, p = 0.0385). Subchronic treadmill training in the rats with hyperhomocysteinemia triggers the colon tissue antioxidant response (by increasing the activities of superoxide dismutase and catalase) and elicits an increase in metabolic enzyme activities (lactate dehydrogenase and malate dehydrogenase). This study offers a comprehensive assessment of the effects of aerobic exercise on colonic tissues in a rat model of hyperhomocysteinemia, evaluating a range of biological indicators including antioxidant enzyme activity, metabolic enzyme activity, and morphometric parameters, which suggested that exercise may confer protective effects at both the physiological and morphological levels. Full article
(This article belongs to the Special Issue Homocysteine in Protein Structure and Function and Human Disease)
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Review

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27 pages, 1931 KiB  
Review
Epigenetic DNA Methylation and Protein Homocysteinylation: Key Players in Hypertensive Renovascular Damage
by Lu Ren, Sathnur Pushpakumar, Hebah Almarshood, Swapan K. Das and Utpal Sen
Int. J. Mol. Sci. 2024, 25(21), 11599; https://doi.org/10.3390/ijms252111599 - 29 Oct 2024
Viewed by 684
Abstract
Hypertension has been a threat to the health of people, the mechanism of which, however, remains poorly understood. It is clinically related to loss of nephron function, glomerular sclerosis, or necrosis, resulting in renal functional declines. The mechanisms underlying hypertension’s development and progression [...] Read more.
Hypertension has been a threat to the health of people, the mechanism of which, however, remains poorly understood. It is clinically related to loss of nephron function, glomerular sclerosis, or necrosis, resulting in renal functional declines. The mechanisms underlying hypertension’s development and progression to organ damage, including hypertensive renal damage, remain to be fully elucidated. As a developing approach, epigenetics has been postulated to elucidate the phenomena that otherwise cannot be explained by genetic studies. The main epigenetic hallmarks, such as DNA methylation, histone acetylation, deacetylation, noncoding RNAs, and protein N-homocysteinylation have been linked with hypertension. In addition to contributing to endothelial dysfunction and oxidative stress, biologically active gases, including NO, CO, and H2S, are crucial regulators contributing to vascular remodeling since their complex interplay conducts homeostatic functions in the renovascular system. Importantly, epigenetic modifications also directly contribute to the pathogenesis of kidney damage via protein N-homocysteinylation. Hence, epigenetic modulation to intervene in renovascular damage is a potential therapeutic approach to treat renal disease and dysfunction. This review illustrates some of the epigenetic hallmarks and their mediators, which have the ability to diminish the injury triggered by hypertension and renal disease. In the end, we provide potential therapeutic possibilities to treat renovascular diseases in hypertension. Full article
(This article belongs to the Special Issue Homocysteine in Protein Structure and Function and Human Disease)
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19 pages, 1740 KiB  
Review
Homocysteine Thiolactone Detoxifying Enzymes and Alzheimer’s Disease
by Hieronim Jakubowski
Int. J. Mol. Sci. 2024, 25(15), 8095; https://doi.org/10.3390/ijms25158095 - 25 Jul 2024
Viewed by 1390
Abstract
Elevated levels of homocysteine (Hcy) and related metabolites are associated with Alzheimer’s disease (AD). Severe hyperhomocysteinemia causes neurological deficits and worsens behavioral and biochemical traits associated with AD. Although Hcy is precluded from entering the Genetic Code by proofreading mechanisms of aminoacyl-tRNA synthetases, [...] Read more.
Elevated levels of homocysteine (Hcy) and related metabolites are associated with Alzheimer’s disease (AD). Severe hyperhomocysteinemia causes neurological deficits and worsens behavioral and biochemical traits associated with AD. Although Hcy is precluded from entering the Genetic Code by proofreading mechanisms of aminoacyl-tRNA synthetases, and thus is a non-protein amino acid, it can be attached to proteins via an N-homocysteinylation reaction mediated by Hcy-thiolactone. Because N-homocysteinylation is detrimental to a protein’s function and biological integrity, Hcy-thiolactone-detoxifying enzymes—PON1, BLMH, BPHL—have evolved. This narrative review provides an account of the biological function of these enzymes and of the consequences of their impairments, leading to the phenotype characteristic of AD. Overall, accumulating evidence discussed in this review supports a hypothesis that Hcy-thiolactone contributes to neurodegeneration associated with a dysregulated Hcy metabolism. Full article
(This article belongs to the Special Issue Homocysteine in Protein Structure and Function and Human Disease)
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