Protein Covalent Modification by Homocysteine: Consequences and Clinical Implications

Sharma, Gunjan; Bhattacharya, Reshmee; Singh, Laishram Rajendrakumar

doi:10.1016/b978-0-12-811913-6.00011-4

Cited by 5 publications

(3 citation statements)

References 157 publications

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“…Interestingly, we observed a decrease in TYMS in our gene validation, which is associated with increased dUMP and DNA instability. This condition results in an imbalance and excessive incorporation of uracil in DNA instead of thymine [37], a process that seems to impair DNA repair mechanisms and contributes to carcinogenesis. One-carbon metabolism can also directly meet the high metabolite requirements for cell proliferation through its by-product, ammonia [17].…”

Section: Discussionmentioning

confidence: 99%

Distinct pattern of one-carbon metabolism, a nutrient-sensitive pathway, in invasive breast cancer: A metabolomic study

et al. 2020

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Altered cell metabolism is a hallmark of cancer and critical for its development. Particularly, activation of one-carbon metabolism in tumor cells can sustain oncogenesis while contributing to epigenetic changes and metabolic adaptation during tumor progression. We assessed whether increased one-carbon metabolism activity is a metabolic feature of invasive ductal carcinoma (IDC). Differences in the metabolic profile between biopsies from IDC (n = 47) and its adjacent tissue (n = 43) and between biopsies from different breast cancer subtypes were assessed by gas spectrometry in targeted (Biocrates Life Science ®) and untargeted approaches, respectively. The metabolomics data were statistically treated using MetaboAnalyst 4.0, SIMCA P+ (version 12.01), Statistica 10 software and t test with p < 0.05. The Cancer Genome Atlas breast cancer dataset was also assessed to validate the metabolomic profile of IDC. Our targeted metabolomics analysis showed distinct metabolomics profiles between IDC and adjacent tissue, where IDC displayed a comparative enrichment of metabolites involved in one-carbon metabolism (serine, glycine, threonine, and methionine) and a predicted increase in the activity of pathways that receive and donate carbon units (i.e., folate, methionine, and homocysteine). In addition, the targeted and untargeted metabolomics analyses showed similar metabolomics profiles between breast cancer subtypes. The gene set enrichment analysis identified different transcription-related functions between IDC and non-tumor tissues that involved onecarbon metabolism. Our data suggest that one-carbon metabolism may be a central pathway in IDC and even in general breast tumors, representing a potential target for its treatment and prevention.

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Section: Discussionmentioning

confidence: 99%

Distinct pattern of one-carbon metabolism, a nutrient-sensitive pathway, in invasive breast cancer: A metabolomic study

et al. 2020

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“…Homocysteine is produced in various cells including proliferating immune-competent cells and endothelial cells [ 27 , 28 , 29 ]. Moreover, Sharma et al found that homocysteine is generated in all cell types [ 30 ]. Endothelial cells can accumulate homocysteine to high intracellular concentrations, in contrast to the plasma homocysteine concentration gradient [ 31 ].…”

Section: Discussionmentioning

confidence: 99%

CRIF1 Deficiency Increased Homocysteine Production by Disrupting Dihydrofolate Reductase Expression in Vascular Endothelial Cells

et al. 2021

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Elevated plasma homocysteine levels can induce vascular endothelial dysfunction; however, the mechanisms regulating homocysteine metabolism in impaired endothelial cells are currently unclear. In this study, we deleted the essential mitoribosomal gene CR6 interacting factor 1 (CRIF1) in human umbilical vein endothelial cells (HUVECs) and mice to induce endothelial cell dysfunction; then, we monitored homocysteine accumulation. We found that CRIF1 downregulation caused significant increases in intracellular and plasma concentrations of homocysteine, which were associated with decreased levels of folate cycle intermediates such as 5-methyltetrahydrofolate (MTHF) and tetrahydrofolate (THF). Moreover, dihydrofolate reductase (DHFR), a key enzyme in folate-mediated metabolism, exhibited impaired activity and decreased protein expression in CRIF1 knockdown endothelial cells. Supplementation with folic acid did not restore DHFR expression levels or MTHF and homocysteine concentrations in endothelial cells with a CRIF1 deletion or DHFR knockdown. However, the overexpression of DHFR in CRIF1 knockdown endothelial cells resulted in decreased accumulation of homocysteine. Taken together, our findings suggest that CRIF1-deleted endothelial cells accumulated more homocysteine, compared with control cells; this was primarily mediated by the disruption of DHFR expression.

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“…Importantly, protein folding/unfolding is not a two‐state reaction, and in most cases, pressure causes proteins to acquire intermediate conformations (Roche et al., 2012). Since the secondary structures of proteins are generally insensitive to it, applying pressure may convert monomeric proteins into a partially unfolded state (“molten‐globule” state), which is characterized by a native‐like secondary structure and a perturbed tertiary structure (Sharma et al., 2019; Silva et al., 2014). Lower pressure intensity (∼ 200–300 MPa) may cause proteins to be present in a pre‐denatured “dry molten‐globule” state with a reversibly and elastically distorted conformation and smaller cavity volume (Somkuti & Smeller, 2013).…”

Section: Effects Of Hhp On Protein Structuresmentioning

confidence: 99%

Effect of high hydrostatic pressure processing on the structure, functionality, and nutritional properties of food proteins: A review

Wang

Yang

Rao

et al. 2022

Comp Rev Food Sci Food Safe

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Proteins are important food ingredients that possess both functional and nutritional properties. High hydrostatic pressure (HHP) is an emerging nonthermal food processing technology that has been subject to great advancements in the last two decades. It is well established that pressure can induce changes in protein folding and oligomerization, and consequently, HHP has the potential to modify the desired protein properties. In this review article, the research progress over the last 15 years regarding the effect of HHP on protein structures, as well as the applications of HHP in modifying protein functionalities (i.e., solubility, water/oil holding capacity, emulsification, foaming and gelation) and nutritional properties (i.e., digestibility and bioactivity) are systematically discussed. Protein unfolding generally occurs during HHP treatment, which can result in increased conformational flexibility and the exposure of interior residues. Through the optimization of HHP and environmental conditions, a balance in protein hydrophobicity and hydrophilicity may be obtained, and therefore, the desired protein functionality can be improved. Moreover, after HHP treatment, there might be greater accessibility of the interior residues to digestive enzymes or the altered conformation of specific active sites, which may lead to modified nutritional properties. However, the practical applications of HHP in developing functional protein ingredients are underutilized and require more research concerning the impact of other food components or additives during HHP

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Protein Covalent Modification by Homocysteine: Consequences and Clinical Implications

Cited by 5 publications

References 157 publications

Distinct pattern of one-carbon metabolism, a nutrient-sensitive pathway, in invasive breast cancer: A metabolomic study

Distinct pattern of one-carbon metabolism, a nutrient-sensitive pathway, in invasive breast cancer: A metabolomic study

CRIF1 Deficiency Increased Homocysteine Production by Disrupting Dihydrofolate Reductase Expression in Vascular Endothelial Cells

Effect of high hydrostatic pressure processing on the structure, functionality, and nutritional properties of food proteins: A review

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