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The Implications of One Carbon and Homocysteine Metabolism in Nutrition...
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The Implications of One Carbon and Homocysteine Metabolism in Nutrition and Health

A special issue of Nutrients (ISSN 2072-6643). This special issue belongs to the section "Nutrition and Metabolism".

Deadline for manuscript submissions: closed (20 November 2021) | Viewed by 19734

Special Issue Editors

Dr. Andrew McCaddon

E-Mail Website
Guest Editor
Faculty of Social and Life Sciences, Wrexham Glyndwr University, Wales, UK
Interests: one-carbon metabolism; vitamin B12; dementia; alzheimer's disease; neurodegenerative diseases; folate; Parkinson's disease
Prof. Dr. Joshua W. Miller

E-Mail Website
Guest Editor
Department of Nutritional Sciences, Rutgers University, New Brunswick, NJ, USA
Interests: B vitamins (folate, B12, B6, B2); homocysteine; one-carbon metabolism; vitamin D; cognitive function; Alzheimer's disease and dementia in aging; blood pressure and hypertension; assessment of B12 status and absorptive capacity
Special Issues, Collections and Topics in MDPI journals

Special Issue Information

Dear Colleagues,

It is now 90 years since homocysteine was first identified as a biologically important amino acid linking methionine and sulfur metabolism.  Since then, over 26,000 research papers have described its relevance to several inborn errors of metabolism, folate, vitamin B12, vitamin B6, and riboflavin status, as well as to diseases as diverse as cardio- and cerebrovascular disease, dementia, renal disease, thyroid disease, and pregnancy complications to name but a few.

Important developments in the field over this time include the first clinical descriptions of homocystinuria and the subsequent discovery of impaired cystathionine β-synthase activity as a causative factor. As the metabolic pathways related to homocysteine became delineated, other important and more common enzymatic defects were described, such as the thermolabile variant of methylenetetrahydrofolate reductase (MTHFR).

The advent of convenient laboratory assays revealed mild-moderate elevation of blood homocysteine concentration in association with several diseases, drugs, disorders and lifestyle factors.  However, in each case, considerable debate still exists concerning its exact contribution to disease pathogenesis.

There have also been important recent developments in the closely related metabolic cycles involving folate, vitamin B12, and B6.  For example, the delineation of sub-cellular one-carbon metabolism in mitochondria and the nucleus, the importance of formate in said metabolism, identification of the transcobalamin receptor and delineation of the sequence of events in intracellular vitamin B12 processing.

This Special Issue welcomes any original research and literature reviews concerning homocysteine in relation to health and disease under the following topics: historical perspectives, homocysteine and related metabolites in cardiovascular and cerebrovascular disease, genetic determinants of hyperhomocysteinaemia, its role in pregnancy complications, cognitive deficits, including dementia and issues and debates concerning its practical assay and relevance in modern routine clinical practice.

In short, this Special Issue will provide both a retrospective and “state of the art” view of homocysteine metabolism and its significance in nutrition and health.

Dr. Andrew McCaddon
Prof. Dr. Joshua W. Miller
Guest Editors

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Keywords

  • • one-carbon metabolism
  • • homocysteine metabolism
  • • vitamin B
  • • folate
  • • cardiovascular and cerebrovascular disease
  • • pregnancy complications
  • • cognitive deficits.

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Published Papers (3 papers)

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Research

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15 pages, 474 KiB  
Article
First Trimester Maternal Homocysteine and Embryonic and Fetal Growth: The Rotterdam Periconception Cohort
by Eleonora Rubini, Katinka M. Snoek, Sam Schoenmakers, Sten P. Willemsen, Kevin D. Sinclair, Melek Rousian and Régine P. M. Steegers-Theunissen
Nutrients 2022, 14(6), 1129; https://doi.org/10.3390/nu14061129 - 8 Mar 2022
Cited by 14 | Viewed by 2778
Abstract
Homocysteine is a marker for derangements in one-carbon metabolism. Elevated homocysteine may represent a causal link between poor maternal nutrition and impaired embryonic and fetal development. We sought to investigate associations between reference range maternal homocysteine and embryonic and fetal growth. We enrolled [...] Read more.
Homocysteine is a marker for derangements in one-carbon metabolism. Elevated homocysteine may represent a causal link between poor maternal nutrition and impaired embryonic and fetal development. We sought to investigate associations between reference range maternal homocysteine and embryonic and fetal growth. We enrolled 1060 singleton pregnancies (555 natural and 505 in vitro fertilization/intracytoplasmic sperm injection (IVF/ICSI) pregnancies) from November 2010 to December 2020. Embryonic and fetal body and head growth was assessed throughout pregnancy using three-dimensional ultrasound scans and virtual reality techniques. Homocysteine was negatively associated with first trimester embryonic growth in the included population (crown-rump length B −0.023 mm, 95% CI −0.038,−0.007, p = 0.004, embryonic volume B −0.011 cm3, 95% CI −0.018,−0.004, p = 0.003). After stratification for conception mode, this association remained in IVF/ICSI pregnancies with frozen embryo transfer (crown-rump length B −0.051 mm, 95% CI −0.081,−0.023, p < 0.001, embryonic volume B −0.024 cm3, 95% CI −0.039,−0.009, p = 0.001), but not in IVF/ICSI pregnancies with fresh embryo transfer and natural pregnancies. Homocysteine was not associated with longitudinal measurements of head growth in first trimester, nor with second and third trimester fetal growth. Homocysteine in the highest quartile (7.3–14.9 µmol/L) as opposed to the lowest (2.5–5.2 µmol/L) was associated with reduced birth weight in natural pregnancies only (B −51.98 g, 95% CI −88.13,−15.84, p = 0.005). In conclusion, high maternal homocysteine within the reference range is negatively associated with first trimester embryonic growth and birth weight, and the effects of homocysteine are dependent on conception mode. Full article
(This article belongs to the Special Issue The Implications of One Carbon and Homocysteine Metabolism in Nutrition and Health)
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18 pages, 2948 KiB  
Article
One-Carbon Metabolism in Alzheimer’s Disease and Parkinson’s Disease Brain Tissue
by Karel Kalecký, Paula Ashcraft and Teodoro Bottiglieri
Nutrients 2022, 14(3), 599; https://doi.org/10.3390/nu14030599 - 29 Jan 2022
Cited by 19 | Viewed by 3399
Abstract
Disruptions in one-carbon metabolism and elevated homocysteine have been previously implicated in the development of dementia associated with Alzheimer’s disease (AD) and Parkinson’s disease (PD). Moreover, a PD diagnosis itself carries substantial risk for the development of dementia. This is the first study [...] Read more.
Disruptions in one-carbon metabolism and elevated homocysteine have been previously implicated in the development of dementia associated with Alzheimer’s disease (AD) and Parkinson’s disease (PD). Moreover, a PD diagnosis itself carries substantial risk for the development of dementia. This is the first study that explores alterations in one-carbon metabolism in AD and PD directly in the human brain frontal cortex, the primary center of cognition. Applying targeted liquid chromatography–tandem mass spectrometry (LC-MS/MS), we analyzed post-mortem samples obtained from 136 subjects (35 AD, 65 PD, 36 controls). We found changes in one-carbon metabolites that indicate inefficient activation of cystathionine β-synthase (CBS) in AD and PD subjects with dementia, the latter seemingly accompanied by a restricted re-methylation flow. Levodopa–carbidopa is known to reduce available vitamin B6, which would explain the hindered CBS activity. We present evidence of temporary non-protein-bound homocysteine accumulation upon levodopa intake in the brain of PD subjects with dementia but not in non-demented PD subjects. Importantly, this homocysteine elevation is not related to levodopa dosage, disease progression, or histopathological markers but exclusively to the dementia status. We hypothesize that this levodopa-induced effect is a direct cause of dementia in PD in susceptible subjects with reduced re-methylation capacity. Furthermore, we show that betaine best correlates with cognitive score even among PD subjects alone and discuss nutritional recommendations to improve one-carbon metabolism function. Full article
(This article belongs to the Special Issue The Implications of One Carbon and Homocysteine Metabolism in Nutrition and Health)
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Review

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15 pages, 877 KiB  
Review
Methylenetetrahydrofolate (MTHFR), the One-Carbon Cycle, and Cardiovascular Risks
by Shanel Raghubeer and Tandi E. Matsha
Nutrients 2021, 13(12), 4562; https://doi.org/10.3390/nu13124562 - 20 Dec 2021
Cited by 100 | Viewed by 12410
Abstract
The 5-10-methylenetetrahydrofolate reductase (MTHFR) enzyme is vital for cellular homeostasis due to its key functions in the one-carbon cycle, which include methionine and folate metabolism and protein, DNA, and RNA synthesis. The enzyme is responsible for maintaining methionine and homocysteine (Hcy) balance to [...] Read more.
The 5-10-methylenetetrahydrofolate reductase (MTHFR) enzyme is vital for cellular homeostasis due to its key functions in the one-carbon cycle, which include methionine and folate metabolism and protein, DNA, and RNA synthesis. The enzyme is responsible for maintaining methionine and homocysteine (Hcy) balance to prevent cellular dysfunction. Polymorphisms in the MTHFR gene, especially C677T, have been associated with various diseases, including cardiovascular diseases (CVDs), cancer, inflammatory conditions, diabetes, and vascular disorders. The C677T MTHFR polymorphism is thought to be the most common cause of elevated Hcy levels, which is considered an independent risk factor for CVD. This polymorphism results in an amino acid change from alanine to valine, which prevents optimal functioning of the enzyme at temperatures above 37 °C. Many studies have been conducted to determine whether there is an association between the C677T polymorphism and increased risk for CVD. There is much evidence in favour of this association, while several studies have concluded that the polymorphism cannot be used to predict CVD development or progression. This review discusses current research regarding the C677T polymorphism and its relationship with CVD, inflammation, diabetes, and epigenetic regulation and compares the evidence provided for and against the association with CVD. Full article
(This article belongs to the Special Issue The Implications of One Carbon and Homocysteine Metabolism in Nutrition and Health)
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