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Homocysteine: Biochemistry, Molecular Biology, and Role in Disease

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A special issue of Biomolecules (ISSN 2218-273X). This special issue belongs to the section "Biological Factors".

Deadline for manuscript submissions: closed (30 October 2020) | Viewed by 47865

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Prof. Dr. Anton Hermann

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Department of Biosciences, University Salzburg, A-5020 Salzburg, Austria
Interests: cell physiology; ion channels; Ca²⁺-activated K⁺ channels; cellular excitability; gasotransmitters
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Prof. Dr. Guzel F. Sitdikova

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Guest Editor

Department of Physiology of Man and Animals, Kazan Federal University, 420008 Kazan, Russia
Interests: neurophysiology; development; homocysteine; ion channels; hydrogen sulfide; synaptic transmission; migraine; pain
Special Issues, Collections and Topics in MDPI journals

Special Issue Information

Dear Colleagues,

Homocysteine is a non-proteinogenic sulfhydryl-containing amino acid derived from methionine and is a homologue of cysteine. The concentration of homocysteine is regulated by two key pathways: remethylation back to methionine or transsulfuration to cysteine with simultaneous production of hydrogen sulfide (H₂S). Homocysteine levels can be increased by different conditions, including genetic factors, diet, life style, several medications, etc. Elevated homocysteine, called hyperhomocysteinemia (hHcy), is associated with a higher risk of neurovascular diseases, dementia, migraines, developmental impairments or epilepsy. Mechanisms underlying neurotoxicity of homocysteine include oxidative stress, DNA damage, protein thiolation, and protein homocysteinylation, triggering apoptosis and excitotoxicity. Recent data indicate inflammation during hHCY with increased levels of several cytokines and changes in DNA methylation.

The gasotransmitter H₂S is implicated in the regulation of numerous physiological functions and possesses neuroprotective potential. Recent data indicate that the level of H₂S decreased under hHcy conditions, which may mediate homocysteine induced neurotoxicity.

This Special Issue will focus on the role of homocysteine in the development of several pathological conditions and the mechanisms of H₂S-mediated cell/neuroprotection.

Prof. Dr. Anton Hermann
Prof. Dr. Guzel F. Sitdikova
Guest Editors

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Keywords

Homocysteine (Hcy)
Hyperhomocysteinemia (hHcy)
Hydrogen sulfide (H2S)
Cellular excitability
Neurodegeneration
Inflammation
Oxidative stress

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Homocysteine: Biochemistry, Molecular Biology, and Role in Disease 2021 in Biomolecules (7 articles)

Published Papers (10 papers)

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Editorial

Jump to: Research, Review

3 pages, 159 KiB

Open AccessEditorial

Homocysteine: Biochemistry, Molecular Biology and Role in Disease

by Anton Hermann and Guzel Sitdikova

Biomolecules 2021, 11(5), 737; https://doi.org/10.3390/biom11050737 - 15 May 2021

Cited by 40 | Viewed by 5093

Abstract

Homocysteine is a non-proteinogenic sulfhydryl-containing amino acid derived from methionine and is a homologue of cysteine [...] Full article

(This article belongs to the Special Issue Homocysteine: Biochemistry, Molecular Biology, and Role in Disease)

Research

Jump to: Editorial, Review

13 pages, 7018 KiB

Open AccessFeature PaperArticle

Kidney Ischemia-Reperfusion Decreases Hydrogen Sulfide and Increases Oxidative Stress in the Heart

by Charith U. B. Wijerathne, Susara Madduma Hewage, Yaw L. Siow and Karmin O

Biomolecules 2020, 10(11), 1565; https://doi.org/10.3390/biom10111565 - 17 Nov 2020

Cited by 15 | Viewed by 3897

Abstract

Patients with acute kidney injury (AKI) have an increased risk of cardiovascular disease. The underlying mechanism of AKI-induced heart injury is not well-understood. Hydrogen sulfide (H₂S), at physiological concentrations, has been implicated in cardiovascular protection through redox balance and vessel relaxation. Cystathionine gamma-lyase (CSE) plays an essential role in H₂S production in the heart. The present study investigated the effect of AKI on H₂S production and oxidative stress in the heart. AKI was induced by kidney ischemia-reperfusion in male and female Sprague-Dawley rats, which led to an increase in plasma creatinine and blood urea nitrogen levels. There was a significant increase in lipid peroxidation and a decrease in glutathione (antioxidant) levels in the plasma and heart, indicating systemic and cardiac oxidative stress. Kidney ischemia-reperfusion reduced CSE expression and H₂S production in the heart. There was a decrease in antioxidant transcription factor Nrf2 level in the nucleus and an increase in inflammatory cytokine (IL-6, TNF-α) expression in the heart. These results suggest that AKI can down-regulate CSE-mediated H₂S production, reduce glutathione levels and increase oxidative stress in the heart. This may contribute to an increased risk of cardiovascular disease in AKI. Full article

(This article belongs to the Special Issue Homocysteine: Biochemistry, Molecular Biology, and Role in Disease)

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16 pages, 1559 KiB

Open AccessFeature PaperArticle

GluN2 Subunit-Dependent Redox Modulation of NMDA Receptor Activation by Homocysteine

by Dmitry A. Sibarov, Sergei I. Boikov, Tatiana V. Karelina and Sergei M. Antonov

Biomolecules 2020, 10(10), 1441; https://doi.org/10.3390/biom10101441 - 14 Oct 2020

Cited by 10 | Viewed by 2897

Abstract

Homocysteine (HCY) molecule combines distinct pharmacological properties as an agonist of N-methyl-d-aspartate receptors (NMDARs) and a reducing agent. Whereas NMDAR activation by HCY was elucidated, whether the redox modulation contributes to its action is unclear. Here, using patch-clamp recording and imaging of intracellular Ca²⁺, we study dithiothreitol (DTT) effects on currents and Ca²⁺ responses activated by HCY through native NMDARs and recombinant diheteromeric GluN1/2A, GluN1/2B, and GluN1/2C receptors. Within a wide range (1–800 μM) of [HCY]s, the concentration–activation relationships for recombinant NMDARs revealed a biphasicness. The high-affinity component obtained between 1 and 100 µM [HCY]s corresponding to the NMDAR activation was not affected by 1 mM DTT. The low-affinity phase observed at [HCY]s above 200 μM probably originated from thiol-dependent redox modulation of NMDARs. The reduction of NMDAR disulfide bonds by either 1 mM DTT or 1 mM HCY decreased GluN1/2A currents activated by HCY. In contrast, HCY-elicited GluN1/2B currents were enhanced due to the remarkable weakening of GluN1/2B desensitization. In fact, cleaving NMDAR disulfide bonds in neurons reversed the HCY-induced Ca²⁺ accumulation, making it dependent on GluN2B- rather than GluN2A-containing NMDARs. Thus, estimated concentrations for the HCY redox effects exceed those in the plasma during intermediate hyperhomocysteinemia but may occur during severe hyperhomocysteinemia. Full article

(This article belongs to the Special Issue Homocysteine: Biochemistry, Molecular Biology, and Role in Disease)

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21 pages, 3282 KiB

Open AccessArticle

Effect of Methionine Diet on Time-Related Metabolic and Histopathological Changes of Rat Hippocampus in the Model of Global Brain Ischemia

by Maria Kovalska, Petra Hnilicova, Dagmar Kalenska, Anna Tomascova, Marian Adamkov and Jan Lehotsky

Biomolecules 2020, 10(8), 1128; https://doi.org/10.3390/biom10081128 - 30 Jul 2020

Cited by 12 | Viewed by 2920

Abstract

Hyperhomocysteinemia (hHcy) represents a strong risk factor for atherosclerosis-associated diseases, like stroke, dementia or Alzheimer’s disease. A methionine (Met)-rich diet leads to an elevated level of homocysteine in plasma and might cause pathological alterations across the brain. The hippocampus is being constantly studied for its selective vulnerability linked with neurodegeneration. This study explores metabolic and histo-morphological changes in the rat hippocampus after global ischemia in the hHcy conditions using a combination of proton magnetic resonance spectroscopy and magnetic resonance-volumetry as well as immunohistochemical analysis. After 4 weeks of a Met-enriched diet at a dose of 2 g/kg of animal weight/day, adult male Wistar rats underwent 4-vessel occlusion lasting for 15 min, followed by a reperfusion period varying from 3 to 7 days. Histo-morphological analyses showed that the subsequent ischemia-reperfusion insult (IRI) aggravates the extent of the sole hHcy-induced degeneration of the hippocampal neurons. Decreased volume in the grey matter, extensive changes in the metabolic ratio, deeper alterations in the number and morphology of neurons, astrocytes and their processes were demonstrated in the hippocampus 7 days post-ischemia in the hHcy animals. Our results suggest that the combination of the two risk factors (hHcy and IRI) endorses and exacerbates the rat hippocampal neurodegenerative processes. Full article

(This article belongs to the Special Issue Homocysteine: Biochemistry, Molecular Biology, and Role in Disease)

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18 pages, 2687 KiB

Open AccessFeature PaperArticle

Calcium Export from Neurons and Multi-Kinase Signaling Cascades Contribute to Ouabain Neuroprotection in Hyperhomocysteinemia

by Maria A. Ivanova, Arina D. Kokorina, Polina D. Timofeeva, Tatiana V. Karelina, Polina A. Abushik, Julia D. Stepanenko, Dmitry A. Sibarov and Sergei M. Antonov

Biomolecules 2020, 10(8), 1104; https://doi.org/10.3390/biom10081104 - 24 Jul 2020

Cited by 9 | Viewed by 2720

Abstract

Pathological homocysteine (HCY) accumulation in the human plasma, known as hyperhomocysteinemia, exacerbates neurodegenerative diseases because, in the brain, this amino acid acts as a persistent N-methyl-d-aspartate receptor agonist. We studied the effects of 0.1–1 nM ouabain on intracellular Ca²⁺ signaling, mitochondrial inner membrane voltage (φ_mit), and cell viability in primary cultures of rat cortical neurons in glutamate and HCY neurotoxic insults. In addition, apoptosis-related protein expression and the involvement of some kinases in ouabain-mediated effects were evaluated. In short insults, HCY was less potent than glutamate as a neurotoxic agent and induced a 20% loss of φ_mit, whereas glutamate caused a 70% decrease of this value. Subnanomolar ouabain exhibited immediate and postponed neuroprotective effects on neurons. (1) Ouabain rapidly reduced the Ca²⁺ overload of neurons and loss of φ_mit evoked by glutamate and HCY that rescued neurons in short insults. (2) In prolonged 24 h excitotoxic insults, ouabain prevented neuronal apoptosis, triggering proteinkinase A and proteinkinase C dependent intracellular neuroprotective cascades for HCY, but not for glutamate. We, therefore, demonstrated here the role of PKC and PKA involving pathways in neuronal survival caused by ouabain in hyperhomocysteinemia, which suggests existence of different appropriate pharmacological treatment for hyperhomocysteinemia and glutamate excitotoxicity. Full article

(This article belongs to the Special Issue Homocysteine: Biochemistry, Molecular Biology, and Role in Disease)

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23 pages, 4961 KiB

Open AccessArticle

Hydrogen Sulfide Alleviates Anxiety, Motor, and Cognitive Dysfunctions in Rats with Maternal Hyperhomocysteinemia via Mitigation of Oxidative Stress

by Olga Yakovleva, Ksenia Bogatova, Renata Mukhtarova, Aleksey Yakovlev, Viktoria Shakhmatova, Elena Gerasimova, Guzel Ziyatdinova, Anton Hermann and Guzel Sitdikova

Biomolecules 2020, 10(7), 995; https://doi.org/10.3390/biom10070995 - 2 Jul 2020

Cited by 37 | Viewed by 3559

Abstract

Hydrogen sulfide (H₂S) is endogenously produced from sulfur containing amino acids, including homocysteine and exerts neuroprotective effects. An increase of homocysteine during pregnancy impairs fetal growth and development of the offspring due to severe oxidative stress. We analyzed the effects of the H₂S donor—sodium hydrosulfide (NaHS) administered to female rats with hyperhomocysteinemia (hHcy) on behavioral impairments and levels of oxidative stress of their offspring. Rats born from females fed with control or high methionine diet, with or without H₂S donor injections were investigated. Rats with maternal hHcy exhibit increased levels of total locomotor activity and anxiety, decreased muscle endurance and motor coordination, abnormalities of fine motor control, as well as reduced spatial memory and learning. Oxidative stress in brain tissues measured by activity of glutathione peroxidases and the level of malondialdehyde was higher in rats with maternal hHcy. Concentrations of H₂S and the activity and expression of the H₂S generating enzyme—cystathionine-beta synthase—were lower compared to the control group. Administration of the H₂S donor to females with hHcy during pregnancy prevented behavioral alterations and oxidative stress of their offspring. The acquisition of behavioral together with biochemical studies will add to our knowledge about homocysteine neurotoxicity and proposes H₂S as a potential agent for therapy of hHcy associated disorders. Full article

(This article belongs to the Special Issue Homocysteine: Biochemistry, Molecular Biology, and Role in Disease)

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17 pages, 3892 KiB

Open AccessArticle

Homocysteine Induces Inflammation in Retina and Brain

by Nehal M. Elsherbiny, Isha Sharma, Dina Kira, Suhib Alhusban, Yara A. Samra, Ravirajsinh Jadeja, Pamela Martin, Mohamed Al-Shabrawey and Amany Tawfik

Biomolecules 2020, 10(3), 393; https://doi.org/10.3390/biom10030393 - 3 Mar 2020

Cited by 88 | Viewed by 8295

Abstract

Homocysteine (Hcy) is an amino acid that requires vitamins B₁₂ and folic acid for its metabolism. Vitamins B₁₂ and folic acid deficiencies lead to hyperhomocysteinemia (HHcy, elevated Hcy), which is linked to the development of diabetic retinopathy (DR), age-related macular degeneration (AMD), and Alzheimer’s disease (AD). The goal of the current study was to explore inflammation as an underlying mechanism of HHcy-induced pathology in age related diseases such as AMD, DR, and AD. Mice with HHcy due to a lack of the enzyme cystathionine-β-synthase (CBS) and wild-type mice were evaluated for microglia activation and inflammatory markers using immuno-fluorescence (IF). Tissue lysates isolated from the brain hippocampal area from mice with HHcy were evaluated for inflammatory cytokines using the multiplex assay. Human retinal endothelial cells, retinal pigment epithelial cells, and monocyte cell lines treated with/without Hcy were evaluated for inflammatory cytokines and NFκB activation using the multiplex assay, western blot analysis, and IF. HHcy induced inflammatory responses in mouse brain, retina, cultured retinal, and microglial cells. NFκB was activated and cytokine array analysis showed marked increase in pro-inflammatory cytokines and downregulation of anti-inflammatory cytokines. Therefore, elimination of excess Hcy or reduction of inflammation is a promising intervention for mitigating damage associated with HHcy in aging diseases such as DR, AMD, and AD. Full article

(This article belongs to the Special Issue Homocysteine: Biochemistry, Molecular Biology, and Role in Disease)

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Review

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14 pages, 3834 KiB

Open AccessReview

S-adenosyl-l-homocysteine Hydrolase: A Structural Perspective on the Enzyme with Two Rossmann-Fold Domains

by Krzysztof Brzezinski

Biomolecules 2020, 10(12), 1682; https://doi.org/10.3390/biom10121682 - 16 Dec 2020

Cited by 19 | Viewed by 3940

Abstract

S-adenosyl-l-homocysteine hydrolase (SAHase) is a major regulator of cellular methylation reactions that occur in eukaryotic and prokaryotic organisms. SAHase activity is also a significant source of l-homocysteine and adenosine, two compounds involved in numerous vital, as well as pathological processes. Therefore, apart from cellular methylation, the enzyme may also influence other processes important for the physiology of particular organisms. Herein, presented is the structural characterization and comparison of SAHases of eukaryotic and prokaryotic origin, with an emphasis on the two principal domains of SAHase subunit based on the Rossmann motif. The first domain is involved in the binding of a substrate, e.g., S-adenosyl-l-homocysteine or adenosine and the second domain binds the NAD⁺ cofactor. Despite their structural similarity, the molecular interactions between an adenosine-based ligand molecule and macromolecular environment are different in each domain. As a consequence, significant differences in the conformation of d-ribofuranose rings of nucleoside and nucleotide ligands, especially those attached to adenosine moiety, are observed. On the other hand, the chemical nature of adenine ring recognition, as well as an orientation of the adenine ring around the N-glycosidic bond are of high similarity for the ligands bound in the substrate- and cofactor-binding domains. Full article

(This article belongs to the Special Issue Homocysteine: Biochemistry, Molecular Biology, and Role in Disease)

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16 pages, 1884 KiB

Open AccessEditor’s ChoiceReview

Implication of Hyperhomocysteinemia in Blood Retinal Barrier (BRB) Dysfunction

by Amany Tawfik, Yara A. Samra, Nehal M. Elsherbiny and Mohamed Al-Shabrawey

Biomolecules 2020, 10(8), 1119; https://doi.org/10.3390/biom10081119 - 29 Jul 2020

Cited by 41 | Viewed by 6443

Abstract

Elevated plasma homocysteine (Hcy) level, known as hyperhomocysteinemia (HHcy) has been linked to different systemic and neurological diseases, well-known as a risk factor for systemic atherosclerosis and cardiovascular disease (CVD) and has been identified as a risk factor for several ocular disorders, such as diabetic retinopathy (DR) and age-related macular degeneration (AMD). Different mechanisms have been proposed to explain HHcy-induced visual dysfunction, including oxidative stress, upregulation of inflammatory mediators, retinal ganglion cell apoptosis, and extracellular matrix remodeling. Our previous studies using in vivo and in vitro models of HHcy have demonstrated that Hcy impairs the function of both inner and outer blood retinal barrier (BRB). Dysfunction of BRB is a hallmark of vision loss in DR and AMD. Our findings highlighted oxidative stress, ER stress, inflammation, and epigenetic modifications as possible mechanisms of HHcy-induced BRB dysfunction. In addition, we recently reported HHcy-induced brain inflammation as a mechanism of blood–brain barrier (BBB) dysfunction and pathogenesis of Alzheimer’s disease (AD). Moreover, we are currently investigating the activation of glutamate receptor N-methyl-d-aspartate receptor (NMDAR) as the molecular mechanism for HHcy-induced BRB dysfunction. This review focuses on the studied effects of HHcy on BRB and the controversial role of HHcy in the pathogenesis of aging neurological diseases such as DR, AMD, and AD. We also highlight the possible mechanisms for such deleterious effects of HHcy. Full article

(This article belongs to the Special Issue Homocysteine: Biochemistry, Molecular Biology, and Role in Disease)

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16 pages, 706 KiB

Open AccessReview

The Link between Homocysteine and Omega-3 Polyunsaturated Fatty Acid: Critical Appraisal and Future Directions

by Gianluca Rizzo and Antonio Simone Laganà

Biomolecules 2020, 10(2), 219; https://doi.org/10.3390/biom10020219 - 2 Feb 2020

Cited by 19 | Viewed by 6091

Abstract

Omega-3 polyunsaturated fatty acids and B vitamins are linked to metabolic and degenerative disorders, such as cardiovascular disease and cognitive decline. In the last two decades, the interplay between B vitamins and omega-3 polyunsaturated fatty acids gained increasing attention. Expression control on enzymes involved in the pathway of homocysteine by polyunsaturated fatty acids has been proposed. The methylation process seems crucial for the metabolism of polyunsaturated fatty acids and their distribution within the body. This review summarizes the available data in humans about the link between homocysteine and omega-3 polyunsaturated fatty acids, with a special focus on the meta-analyses of randomized clinical trials. Even if the paucity of available information about the topic does not allow for definitive conclusions, a synergic action between polyunsaturated fatty acids and B vitamins may play a key role in regulating several metabolic pathways. This element could explain a stronger action on homocysteine levels when omega-3 polyunsaturated fatty acids and B vitamins are supplemented simultaneously. To date, a robust rationale of intervention to prevent metabolic diseases is lacking and could be beneficial for individual health and healthcare policy. Full article

(This article belongs to the Special Issue Homocysteine: Biochemistry, Molecular Biology, and Role in Disease)

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