One-carbon metabolism: An aging-cancer crossroad for the gerosuppressant metformin

Menendez, Javier A.; Joven, Jorge

doi:10.18632/aging.100523

Cited by 19 publications

(13 citation statements)

References 32 publications

(36 reference statements)

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“…The altered purine metabolism may have also caused the change in the AMP/ATP ratio in DJB rats (22,23). Indeed, we observed an increased AMP/ATP ratio in the DJB group in the current study.…”

Section: Discussionsupporting

confidence: 46%

Changes in one-carbon metabolism after duodenal-jejunal bypass surgery

Jung

Lee

et al. 2016

American Journal of Physiology-Endocrinology and Metabolism

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GS. Changes in one-carbon metabolism after duodenal-jejunal bypass surgery. Am J Physiol Endocrinol Metab 310: E624 -E632, 2016. First published January 19, 2016 doi:10.1152/ajpendo.00260.2015.-Bariatric surgery alleviates obesity and ameliorates glucose tolerance. Using metabolomic and proteomic profiles, we evaluated metabolic changes in serum and liver tissue after duodenal-jejunal bypass (DJB) surgery in rats fed a normal chow diet. We found that the levels of vitamin B 12 in the sera of DJB rates were decreased. In the liver of DJB rats, betaine-homocysteine S-methyltransferase levels were decreased, whereas serine, cystathionine, cysteine, glutathione, cystathionine ␤-synthase, glutathione S-transferase, and aldehyde dehydrogenase levels were increased. These results suggested that DJB surgery enhanced trans-sulfuration and its consecutive reactions such as detoxification and the scavenging activities of reactive oxygen species. In addition, DJB rats showed higher levels of purine metabolites such as ATP, ADP, AMP, and inosine monophosphate. Decreased guanine deaminase, as well as lower levels of hypoxanthine, indicated that DJB surgery limited the purine degradation process. In particular, the AMP/ATP ratio and phosphorylation of AMP-activated protein kinase increased after DJB surgery, which led to enhanced energy production and increased catabolic pathway activity, such as fatty acid oxidation and glucose transport. This study shows that bariatric surgery altered transsulfuration and purine metabolism in the liver. Characterization of these mechanisms increases our understanding of the benefits of bariatric surgery. gastric bypass surgery; metabolomics; proteomics; metabolism DIABETES AFFECTS ALMOST 10% of the general population and is a leading cause of disability, morbidity, and mortality (15). Although glycemic control and risk factor management have improved, the prevalence of diabetes is still increasing (8, 9). Furthermore, current drug-based therapies for diabetes rarely lead to remission. Thus, there is an urgent need for new therapeutic options.Bariatric surgery provides a reliable treatment that results in substantial and sustained weight loss in morbidly obese patients and provides a substantial improvement in cases of type 2 diabetes mellitus (T2DM) (5, 6). Bariatric surgery is significantly better than intensive medical therapy for the glycemic control of T2DM at 1-2 years (10,13,24,38). However, the mechanism by which bariatric surgery results in the remission of T2DM remains unclear. Moreover, given that the initial body mass index and postoperative weight loss values are poor predictors of the efficacy of bariatric surgery in patients with diabetes and metabolic syndrome (27, 41), the improvement in glycemia after bariatric surgery is not simply a consequence of sustained weight loss. Therefore, understanding the underlying mechanism of bariatric surgery with respect to the resolution of T2DM is important for the development of more effective and less invasive T2DM therapeutic strategie...

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Section: Discussionsupporting

confidence: 46%

Changes in one-carbon metabolism after duodenal-jejunal bypass surgery

Jung

Lee

et al. 2016

American Journal of Physiology-Endocrinology and Metabolism

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“…One example is that of metformin, an antidiabetic and gerosuppressant drug that has been suggested to work against AD, even if with conflicting results [63,64]. Indeed, metformin was shown to impair one-carbon metabolism in a manner similar to the antifolate class of chemotherapy drugs [65,66]. Other factors that could affect folate metabolism in aged individuals are dietary supplements containing folate, B-vitamins, or similar [67].…”

Section: Discussionmentioning

confidence: 99%

Application of Artificial Neural Networks to Investigate One-Carbon Metabolism in Alzheimer’s Disease and Healthy Matched Individuals

Coppedè

Grossi²,

Buscema

et al. 2013

PLoS ONE

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Folate metabolism, also known as one-carbon metabolism, is required for several cellular processes including DNA synthesis, repair and methylation. Impairments of this pathway have been often linked to Alzheimer’s disease (AD). In addition, increasing evidence from large scale case-control studies, genome-wide association studies, and meta-analyses of the literature suggest that polymorphisms of genes involved in one-carbon metabolism influence the levels of folate, homocysteine and vitamin B12, and might be among AD risk factors. We analyzed a dataset of 30 genetic and biochemical variables (folate, homocysteine, vitamin B12, and 27 genotypes generated by nine common biallelic polymorphisms of genes involved in folate metabolism) obtained from 40 late-onset AD patients and 40 matched controls to assess the predictive capacity of Artificial Neural Networks (ANNs) in distinguish consistently these two different conditions and to identify the variables expressing the maximal amount of relevant information to the condition of being affected by dementia of Alzheimer’s type. Moreover, we constructed a semantic connectivity map to offer some insight regarding the complex biological connections among the studied variables and the two conditions (being AD or control). TWIST system, an evolutionary algorithm able to remove redundant and noisy information from complex data sets, selected 16 variables that allowed specialized ANNs to discriminate between AD and control subjects with over 90% accuracy. The semantic connectivity map provided important information on the complex biological connections among one-carbon metabolic variables highlighting those most closely linked to the AD condition.

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“…Summarizing some of the evidence for folate pathway-mediated effects: 1) Elevated homocysteine levels have been observed in patients undergoing biguanide treatment 29, 30 that have been reversed with supplemental folate treatment 31 . 2) Parallels between the responses to biguanides and anti-folate drugs such as methotrexate have often been noted 32, 33 . 3) Conversely, metabolomic analyses of patients receiving anti-folate drugs such as methotrexate (MTX) exhibit a response consistent with activation of AMP-activated kinase (AMPK), considered a major indirect target of metformin 34 .…”

Section: Introductionmentioning

confidence: 99%

A Structural Basis for Biguanide Activity

et al. 2017

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Metformin is the most commonly prescribed treatment for Type II diabetes and related disorders, however molecular insights into its mode(s) of action have been limited by an absence of structural data. Structural considerations along with an increasing body of literature demonstrating its effects on one-carbon metabolism suggest the possibility of folate mimicry and anti-folate activity. Motivated by increasing recognition that anti-diabetic biguanides may act directly upon the gut microbiome, we have determined structures of the complexes formed between the anti-diabetic biguanides: phenformin, buformin, and metformin and E. coli dihydrofolate reductase (ecDHFR) based on NMR, crystallographic and molecular modeling studies. Inter-ligand Overhauser effects indicate that metformin can form ternary complexes with p-aminobenzoyl-L-glutamate (pABG) as well as other ligands that occupy the region of the folate binding site that interacts with pABG, however DHFR inhibition is not cooperative. The biguanides inhibit the activity of ecDHFR competitively, with the phenformin inhibition constant 100-fold lower than that of metformin. This inhibition may be significant at concentrations present in the gut of treated individuals, and inhibition of DHFR in intestinal mucosal cells may also occur if accumulated levels are sufficient. Perturbation of folate homeostasis can alter the pyridine nucleotide redox ratios that are important regulators of cellular metabolism.

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One-carbon metabolism: An aging-cancer crossroad for the gerosuppressant metformin

Cited by 19 publications

References 32 publications

Changes in one-carbon metabolism after duodenal-jejunal bypass surgery

Changes in one-carbon metabolism after duodenal-jejunal bypass surgery

Application of Artificial Neural Networks to Investigate One-Carbon Metabolism in Alzheimer’s Disease and Healthy Matched Individuals

A Structural Basis for Biguanide Activity

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