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Vitamins and Derived Cofactors: Transport, Metabolism, Assembly and Deficiencies

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

Deadline for manuscript submissions: closed (25 July 2024) | Viewed by 15271

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Prof. Dr. Maria Barile

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Department of Bioscience, Biotechnology and Biopharmaceutics, University of Bari A. Moro, Via Orabona, 4, I-70126 Bari, Italy
Interests: Rf and derived cofactors; transport metabolism; cofactor assembly; related human disorders
Special Issues, Collections and Topics in MDPI journals

Prof. Michele Galluccio

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Department DiBEST (Biologia, Ecologia, Scienze della Terra), Unity of Molecular Biology, University of Calabria, Via P. Bucci 6C, 87036 Arcavacata di Rende, Italy
Interests: protein expression and purification; structure function studies; FAD synthase isoforms; SLC transporters; enzymes
Special Issues, Collections and Topics in MDPI journals

Special Issue Information

Dear Colleagues,

The intra-cellular availability of vitamin-derived cofactors is strictly required for the correct structure and function of a great number of enzymes in all living organisms. Nevertheless, many aspects concerning vitamins and/or their derived cofactor absorption, transport, metabolism and intracellular trafficking are still awaiting elucidation, as well as the mode of insertion of cofactors into nascent polypeptides. Given the relevance of these essential molecules for cellular functionality, it is not surprising that a number of severe human pathological conditions, such as cancer, neurodegeneration and certain inborn errors of metabolism, are related to alterations to cofactor availability; therefore, further research is necessary to define the molecular consequences of alterations to the individual steps of cofactor delivery to search for a possible therapeutic intervention on the related pathologies.

This Special Issue aims to provide a sort of compendium on the recent advances in the fields of enzymology, cellular biochemistry and molecular biology related to vitamins and their derived cofactors. Considering the wide spectrum of functions that cofactor-requiring enzymes can have in cells, the translation of basic knowledge to pharmacology and pathophysiology will also be addressed.

Prof. Dr. Maria Barile
Prof. Michele Galluccio
Guest Editors

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Keywords

vitamin
cofactor
transporter
assembly
vitamin-responsive inborn errors of metabolism

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Published Papers (9 papers)

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Research

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12 pages, 702 KiB

Open AccessArticle

Iron Deficiency Is Associated with Elevated Parathormone Levels, Low Vitamin D Status, and Risk of Bone Loss in Omnivores and Plant-Based Diet Consumers

by M. Pilar Vaquero, Elena García-Maldonado, Angélica Gallego-Narbón, Belén Zapatera, Alexandra Alcorta and Miriam Martínez-Suárez

Int. J. Mol. Sci. 2024, 25(19), 10290; https://doi.org/10.3390/ijms251910290 - 24 Sep 2024

Viewed by 387

Abstract

A cross-sectional study was performed in healthy adults (mean age 28 y, 67% women) whose habitual diet was an omnivore, lacto-ovo vegetarian, or vegan diet. The total sample (n = 297) was divided into two groups according to the parathormone (PTH) cut-off value of 65 pg/mL of either normal-PTH (n = 228) or high-PTH (n = 69). Vitamin D status (25-hydroxycholecalciferol, 25-OHD), PTH, and bone formation (bone alkaline phosphatase, BAP) and bone resorption (N-telopeptides of type I collagen, NTx) markers were determined. Hematocrit, erythrocytes, hemoglobin, platelets, serum iron, serum transferrin, transferrin saturation, and serum ferritin were also measured. In the total sample, 25-OHD and PTH were negatively correlated, and all subjects with high PTH presented vitamin D insufficiency (25-OHD < 75 nmol/L). High bone remodeling was observed in the high-PTH group, with significantly higher NTx and marginally higher BAP compared to the normal-PTH group. Hematocrit and ferritin were significantly lower in the high-PTH compared to the normal-PTH group. However, serum iron was higher in the high-PTH group, which was only observed for the lacto-ovo vegetarian and vegan subjects. It is concluded that both low vitamin D and low iron status are associated with elevated PTH and bone resorption, more in vegetarians than omnivores, which is in line with the hypothesis that chronic iron deficiency in adulthood mainly predisposes to osteoporosis in postmenopausal women and the elderly. Full article

(This article belongs to the Special Issue Vitamins and Derived Cofactors: Transport, Metabolism, Assembly and Deficiencies)

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11 pages, 1453 KiB

Open AccessArticle

Exploring the Roles of Vitamins C and D and Etifoxine in Combination with Citalopram in Depression/Anxiety Model: A Focus on ICAM-1, SIRT1 and Nitric Oxide

by Omar Gammoh, Aseel Ibrahim, Ala Yehya, Abdelrahim Alqudah, Esam Qnais, Sara Altaber, Osama Abo Alrob, Alaa A. A. Aljabali and Murtaza M. Tambuwala

Int. J. Mol. Sci. 2024, 25(4), 1960; https://doi.org/10.3390/ijms25041960 - 6 Feb 2024

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Abstract

The study of intercellular adhesion molecule-1 (ICAM-1) and SIRT1, a member of the sirtuin family with nitric oxide (NO), is emerging in depression and anxiety. As with all antidepressants, the efficacy is delayed and inconsistent. Ascorbic acid (AA) and vitamin D (D) showed antidepressant properties, while etifoxine (Etx), a GABAA agonist, alleviates anxiety symptoms. The present study aimed to investigate the potential augmentation of citalopram using AA, D and Etx and related the antidepressant effect to brain and serum ICAM-1, SIRT1 and NO in an animal model. BALB/c mice were divided into naive, control, citalopram, citalopram + etx, citalopram + AA, citalopram + D and citalopram + etx + AA + D for 7 days. On the 8th day, the mice were restrained for 8 h, followed by a forced swim test and marble burying test before scarification. Whole-brain and serum expression of ICAM-1, Sirt1 and NO were determined. Citalopram’s antidepressant and sedative effects were potentiated by ascorbic acid, vitamin D and etifoxine alone and in combination (p < 0.05), as shown by the decreased floating time and rearing frequency. Brain NO increased significantly (p < 0.05) in depression and anxiety and was associated with an ICAM-1 increase versus naive (p < 0.05) and a Sirt1 decrease (p < 0.05) versus naive. Both ICAM-1 and Sirt1 were modulated by antidepressants through a non-NO-dependent pathway. Serum NO expression was unrelated to serum ICAM-1 and Sirt1. Brain ICAM-1, Sirt1 and NO are implicated in depression and are modulated by antidepressants. Full article

(This article belongs to the Special Issue Vitamins and Derived Cofactors: Transport, Metabolism, Assembly and Deficiencies)

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Review

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25 pages, 1059 KiB

Open AccessReview

Vitamin B₁₂ Metabolism: A Network of Multi-Protein Mediated Processes

by Patryk Mucha, Filip Kus, Dominik Cysewski, Ryszard T. Smolenski and Marta Tomczyk

Int. J. Mol. Sci. 2024, 25(15), 8021; https://doi.org/10.3390/ijms25158021 - 23 Jul 2024

Viewed by 1194

Abstract

The water-soluble vitamin, vitamin B₁₂, also known as cobalamin, plays a crucial role in cellular metabolism, particularly in DNA synthesis, methylation, and mitochondrial functionality. Its deficiency can lead to hematological and neurological disorders; however, the manifestation of these clinical outcomes is relatively late. It leads to difficulties in the early diagnosis of vitamin B₁₂ deficiency. A prolonged lack of vitamin B₁₂ may have severe consequences including increased morbidity to neurological and cardiovascular diseases. Beyond inadequate dietary intake, vitamin B₁₂ deficiency might be caused by insufficient bioavailability, blood transport disruptions, or impaired cellular uptake and metabolism. Despite nearly 70 years of knowledge since the isolation and characterization of this vitamin, there are still gaps in understanding its metabolic pathways. Thus, this review aims to compile current knowledge about the crucial proteins necessary to efficiently accumulate and process vitamin B₁₂ in humans, presenting these systems as a multi-protein network. The epidemiological consequences, diagnosis, and treatment of vitamin B₁₂ deficiency are also highlighted. We also discuss clinical warnings of vitamin B₁₂ deficiency based on the ongoing test of specific moonlighting proteins engaged in vitamin B₁₂ metabolic pathways. Full article

(This article belongs to the Special Issue Vitamins and Derived Cofactors: Transport, Metabolism, Assembly and Deficiencies)

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22 pages, 1719 KiB

Open AccessReview

The Significance of Genetically Determined Methylation and Folate Metabolism Disorders in the Pathogenesis of Coronary Artery Disease: A Target for New Therapies?

by Agnieszka Pietruszyńska-Reszetarska, Robert Pietruszyński and Robert Irzmański

Int. J. Mol. Sci. 2024, 25(13), 6924; https://doi.org/10.3390/ijms25136924 - 25 Jun 2024

Cited by 1 | Viewed by 697

Abstract

Methylation is a biochemical process involving the addition of a methyl group (-CH₃) to various chemical compounds. It plays a crucial role in maintaining the homeostasis of the endothelium, which lines the interior surface of blood vessels, and has been linked, among other conditions, to coronary artery disease (CAD). Despite significant progress in CAD diagnosis and treatment, intensive research continues into genotypic and phenotypic CAD biomarkers. This review explores the significance of the methylation pathway and folate metabolism in CAD pathogenesis, with a focus on endothelial dysfunction resulting from deficiency in the active form of folate (5-MTHF). We discuss emerging areas of research into CAD biomarkers and factors influencing the methylation process. By highlighting genetically determined methylation disorders, particularly the MTHFR polymorphism, we propose the potential use of the active form of folate (5-MTHF) as a novel CAD biomarker and personalized pharmaceutical for selected patient groups. Our aim is to improve the identification of individuals at high risk of CAD and enhance their prognosis. Full article

(This article belongs to the Special Issue Vitamins and Derived Cofactors: Transport, Metabolism, Assembly and Deficiencies)

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29 pages, 4053 KiB

Open AccessReview

Vitamin Status in Patients with Phenylketonuria: A Systematic Review and Meta-Analysis

by Kamila Bokayeva, Małgorzata Jamka, Dariusz Walkowiak, Monika Duś-Żuchowska, Karl-Heinz Herzig and Jarosław Walkowiak

Int. J. Mol. Sci. 2024, 25(10), 5065; https://doi.org/10.3390/ijms25105065 - 7 May 2024

Cited by 2 | Viewed by 1416

Abstract

The published data on the vitamin status of patients with phenylketonuria (PKU) is contradictory; therefore, this systematic review and meta-analysis evaluated the vitamin status of PKU patients. A comprehensive search of multiple databases (PubMed, Web of Sciences, Cochrane, and Scopus) was finished in March 2024. The included studies compared vitamin levels between individuals diagnosed with early-treated PKU and healthy controls while excluding pregnant and lactating women, untreated PKU or hyperphenylalaninemia cases, control groups receiving vitamin supplementation, PKU patients receiving tetrahydrobiopterin or pegvaliase, and conference abstracts. The risk of bias in the included studies was assessed by the Newcastle–Ottawa scale. The effect sizes were expressed as standardised mean differences. The calculation of effect sizes with 95% CI using fixed-effects models and random-effects models was performed. A p-value < 0.05 was considered statistically significant. The study protocol was registered in the PROSPERO database (CRD42024519589). Out of the initially identified 11,086 articles, 24 met the criteria. The total number of participants comprised 770 individuals with PKU and 2387 healthy controls. The meta-analyses of cross-sectional and case–control studies were conducted for vitamin B12, D, A, E, B6 and folate levels. PKU patients demonstrated significantly higher folate levels (random-effects model, SMD: 1.378, 95% CI: 0.436, 2.320, p = 0.004) and 1,25-dihydroxyvitamin D concentrations (random-effects model, SMD: 2.059, 95% CI: 0.250, 3.868, p = 0.026) compared to the controls. There were no significant differences in vitamin A, E, B6, B12 or 25-dihydroxyvitamin D levels. The main limitations of the evidence include a limited number of studies and their heterogeneity and variability in patients’ compliance. Our findings suggest that individuals with PKU under nutritional guidance can achieve a vitamin status comparable to that of healthy subjects. Our study provides valuable insights into the nutritional status of PKU patients, but further research is required to confirm these findings and explore additional factors influencing vitamin status in PKU. Full article

(This article belongs to the Special Issue Vitamins and Derived Cofactors: Transport, Metabolism, Assembly and Deficiencies)

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23 pages, 5517 KiB

Open AccessReview

Pyridoxal 5′-Phosphate Biosynthesis by Pyridox-(am)-ine 5′-Phosphate Oxidase: Species-Specific Features

by Maribel Rivero, Nerea Novo and Milagros Medina

Int. J. Mol. Sci. 2024, 25(6), 3174; https://doi.org/10.3390/ijms25063174 - 9 Mar 2024

Viewed by 1665

Abstract

Enzymes reliant on pyridoxal 5′-phosphate (PLP), the metabolically active form of vitamin B₆, hold significant importance in both biology and medicine. They facilitate various biochemical reactions, particularly in amino acid and neurotransmitter metabolisms. Vitamin B₆ is absorbed by organisms in its non-phosphorylated form and phosphorylated within cells via pyridoxal kinase (PLK) and pyridox-(am)-ine 5′-phosphate oxidase (PNPOx). The flavin mononucleotide-dependent PNPOx enzyme converts pyridoxine 5′-phosphate and pyridoxamine 5′-phosphate into PLP. PNPOx is vital for both biosynthesis and salvage pathways in organisms producing B₆ vitamers. However, for those depending on vitamin B₆ as a nutrient, PNPOx participates only in the salvage pathway. Transferring the PLP produced via PNPOx to client apo-enzymes is indispensable for their catalytic function, proper folding and targeting of specific organelles. PNPOx activity deficiencies due to inborn errors lead to severe neurological pathologies, particularly neonatal epileptic encephalopathy. PNPOx maintains PLP homeostasis through highly regulated mechanisms, including structural alterations throughout the catalytic cycle and allosteric PLP binding, influencing substrate transformation at the active site. Elucidation at the molecular level of the mechanisms underlying PNPOx activity deficiencies is a requirement to develop personalized approaches to treat related disorders. Finally, despite shared features, the few PNPOx enzymes molecularly and functionally studied show species-specific regulatory properties that open the possibility of targeting it in pathogenic organisms. Full article

(This article belongs to the Special Issue Vitamins and Derived Cofactors: Transport, Metabolism, Assembly and Deficiencies)

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21 pages, 1910 KiB

Open AccessReview

The Potential Use of Vitamin D3 and Phytochemicals for Their Anti-Ageing Effects

by Kazuki Santa, Yoshio Kumazawa, Kenji Watanabe and Isao Nagaoka

Int. J. Mol. Sci. 2024, 25(4), 2125; https://doi.org/10.3390/ijms25042125 - 9 Feb 2024

Cited by 1 | Viewed by 4711

Abstract

Unlike other vitamins, vitamin D3 is synthesised in skin cells in the body. Vitamin D3 has been known as a bone-related hormone. Recently, however, it has been considered as an immune vitamin. Vitamin D3 deficiency influences the onset of a variety of diseases. Vitamin D3 regulates the production of proinflammatory cytokines such as tumour necrosis factor-α (TNF-α) through binding to vitamin D receptors (VDRs) in immune cells. Since blood levels of vitamin D3 (25-OH-D3) were low in coronavirus disease 2019 (COVID-19) patients, there has been growing interest in the importance of vitamin D3 to maintaining a healthy condition. On the other hand, phytochemicals are compounds derived from plants with over 7000 varieties and have various biological activities. They mainly have health-promoting effects and are classified as terpenoids, carotenoids, flavonoids, etc. Flavonoids are known as the anti-inflammatory compounds that control TNF-α production. Chronic inflammation is induced by the continuous production of TNF-α and is the fundamental cause of diseases like obesity, dyslipidaemia, diabetes, heart and brain diseases, autoimmune diseases, Alzheimer’s disease, and cancer. In addition, the ageing process is induced by chronic inflammation. This review explains the cooperative effects of vitamin D3 and phytochemicals in the suppression of inflammatory responses, how it balances the natural immune response, and its link to anti-ageing effects. In addition, vitamin D3 and phytochemicals synergistically contribute to anti-ageing by working with ageing-related genes. Furthermore, prevention of ageing processes induced by the chronic inflammation requires the maintenance of healthy gut microbiota, which is related to daily dietary habits. In this regard, supplementation of vitamin D3 and phytochemicals plays an important role. Recently, the association of the prevention of the non-disease condition called “ME-BYO” with the maintenance of a healthy condition has been an attractive regimen, and the anti-ageing effect discussed here is important for a healthy and long life. Full article

(This article belongs to the Special Issue Vitamins and Derived Cofactors: Transport, Metabolism, Assembly and Deficiencies)

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22 pages, 715 KiB

Open AccessReview

Micronutrient Deficiency in Inherited Metabolic Disorders Requiring Diet Regimen: A Brief Critical Review

by Albina Tummolo, Rosa Carella, Donatella De Giovanni, Giulia Paterno, Simonetta Simonetti, Maria Tolomeo, Piero Leone and Maria Barile

Int. J. Mol. Sci. 2023, 24(23), 17024; https://doi.org/10.3390/ijms242317024 - 30 Nov 2023

Cited by 1 | Viewed by 1854

Abstract

Many inherited metabolic disorders (IMDs), including disorders of amino acid, fatty acid, and carbohydrate metabolism, are treated with a dietary reduction or exclusion of certain macronutrients, putting one at risk of a reduced intake of micronutrients. In this review, we aim to provide available evidence on the most common micronutrient deficits related to specific dietary approaches and on the management of their deficiency, in the meanwhile discussing the main critical points of each nutritional supplementation. The emerging concepts are that a great heterogeneity in clinical practice exists, as well as no univocal evidence on the most common micronutrient abnormalities. In phenylketonuria, for example, micronutrients are recommended to be supplemented through protein substitutes; however, not all formulas are equally supplemented and some of them are not added with micronutrients. Data on pyridoxine and riboflavin status in these patients are particularly scarce. In long-chain fatty acid oxidation disorders, no specific recommendations on micronutrient supplementation are available. Regarding carbohydrate metabolism disorders, the difficult-to-ascertain sugar content in supplementation formulas is still a matter of concern. A ketogenic diet may predispose one to both oligoelement deficits and their overload, and therefore deserves specific formulations. In conclusion, our overview points out the lack of unanimous approaches to micronutrient deficiencies, the need for specific formulations for IMDs, and the necessity of high-quality studies, particularly for some under-investigated deficits. Full article

(This article belongs to the Special Issue Vitamins and Derived Cofactors: Transport, Metabolism, Assembly and Deficiencies)

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15 pages, 634 KiB

Open AccessPerspective

Does Vitamin B6 Act as an Exercise Mimetic in Skeletal Muscle?

by Norihisa Kato, Yongshou Yang, Chanikan Bumrungkit and Thanutchaporn Kumrungsee

Int. J. Mol. Sci. 2024, 25(18), 9962; https://doi.org/10.3390/ijms25189962 - 15 Sep 2024

Viewed by 607

Abstract

Marginal vitamin B6 (B6) deficiency is common in various segments worldwide. In a super-aged society, sarcopenia is a major concern and has gained significant research attention focused on healthy aging. To date, the primary interventions for sarcopenia have been physical exercise therapy. Recent evidence suggests that inadequate B6 status is associated with an increased risk of sarcopenia and mortality among older adults. Our previous study showed that B6 supplementation to a marginal B6-deficient diet up-regulated the expression of various exercise-induced genes in the skeletal muscle of rodents. Notably, a supplemental B6-to-B6-deficient diet stimulates satellite cell-mediated myogenesis in rodents, mirroring the effects of physical exercise. These findings suggest the potential role of B6 as an exercise-mimetic nutrient in skeletal muscle. To test this hypothesis, we reviewed relevant literature and compared the roles of B6 and exercise in muscles. Here, we provide several pieces of evidence supporting this hypothesis and discuss the potential mechanisms behind the similarities between the effects of B6 and exercise on muscle. This research, for the first time, provides insight into the exercise-mimetic roles of B6 in skeletal muscle. Full article

(This article belongs to the Special Issue Vitamins and Derived Cofactors: Transport, Metabolism, Assembly and Deficiencies)

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