bims-glucam 2025-01-12 papers

bims-glucam

Biomed News

on Glutamine cancer metabolism

Issue of 2025–01–12
fifteen papers selected by
Sreeparna Banerjee, Middle East Technical University

Coordination of Glucose and Glutamine Metabolism in Tendon is Lost in Aging.
Folate-targeted nanoparticles for glutamine metabolism inhibition enhance anti-tumor immunity and suppress tumor growth in ovarian cancer.
Glutamine metabolism is systemically different between primary and induced pluripotent stem cell-derived brain microvascular endothelial cells.
Inhibition of Glutaminase 1 Reduces M1 Macrophage Polarization to Protect Against Monocrotaline-Induced Pulmonary Arterial Hypertension.
The role of GOT1 in cancer metabolism.
Metabolic adaptation of myeloid cells in the glioblastoma microenvironment.
Metabolic Crossroad Between Macrophages and Cancer Cells: Overview of Hepatocellular Carcinoma.
Altered Cellular Metabolism Is a Consequence of Loss of the Ataxia-Linked Protein Sacsin.
α-Ketoglutarate dehydrogenase is a therapeutic vulnerability in acute myeloid leukemia.
Tumor metabolic regulators: key drivers of metabolic reprogramming and the promising targets in cancer therapy.
Impact of a glutamine-enriched peptide formula on gastrointestinal toxicity and on the interruption of oncologic treatment in patients with adenocarcinoma of the rectum.
RTN4IP1 Contributes to ESCC via Regulation of Amino Acid Transporters.
HMB/Arg/Gln may improve short-term outcomes after esophagectomy in patients with thoracic esophageal cancer.
Metabolomic Profiling of Oral Potentially Malignant Disorders and Its Clinical Values.
Genetic and biochemical characterization of a radical SAM enzyme required for post-translational glutamine methylation of methyl-coenzyme M reductase.

bioRxiv. 2024 Dec 20. pii: 2024.12.19.629426. [Epub ahead of print]

Coordination of Glucose and Glutamine Metabolism in Tendon is Lost in Aging.

Samuel J Mlawer, Felicia R Pinto, Katie J Sikes, Brianne K Connizzo.

Tendinopathy is an age-associated degenerative disease characterized by a loss in extracellular matrix (ECM). Since glucose and glutamine metabolism is critical to amino acid synthesis and known to be altered in aging, we sought to investigate if age-related changes in metabolism are linked to changes in ECM remodeling. We exposed young and aged tendon explants to various concentrations of glucose and glutamine to observe changes in metabolic processing (enzyme levels, gene expression, etc.) and matrix biosynthesis. Interestingly, we found that glutamine processing is affected by glucose levels, but this effect was lost with aging. ECM synthesis was altered in a protein-dependent manner by increased glucose and glutamine levels in young tendons. However, these changes were not conserved in aged tendons. Overall, our work suggests that glucose and glutamine metabolism is important for ECM homeostasis, and age-related changes in nutrient metabolism could be a key driver of tendon degeneration.

DOI: https://doi.org/10.1101/2024.12.19.629426
J Control Release. 2025 Jan 08. pii: S0168-3659(24)00928-3. [Epub ahead of print]379 89-104

Folate-targeted nanoparticles for glutamine metabolism inhibition enhance anti-tumor immunity and suppress tumor growth in ovarian cancer.

Shuning Chen, Yu Jiang, Jiao Zheng, Pan Li, Maoyu Liu, Yi Zhu, Shenyin Zhu, Shufang Chang.

  Ovarian cancer (OC) is a highly malignant gynecological tumor, and its effective treatment is frequently impeded by drug resistance and recurrent tumor growth. The reprogramming of glutamine metabolism in ovarian cancer is closely associated with tumor progression and the immunosuppressive tumor microenvironment. Recently, targeting metabolic reprogramming has emerged as a promising approach for cancer therapy. However, the application of such therapies is often constrained by their significant toxicity to normal tissues. In this study, we fabricated folate-targeted nanoparticles (FA-DCNPs) that co-encapsulate the glutamine metabolism inhibitor 6-diazo-5-oxo-L-norleucine (DON) and calcium carbonate (CaCO3). These nanoparticles alleviate damage to normal tissues by specifically targeting tumor cells via folate receptors (FOLR) mediation. Under acidic conditions, the FA-DCNPs release DON and Ca2+, generating a synergistic anti-tumor effect by impeding glutamine metabolism and inducing calcium overload. Additionally, FA-DCNPs target M2 phenotype tumor-associated macrophages (TAMs) via FOLR2, attenuating M2-TAMs activity. When partially phagocytosed by M0-TAMs, the nanoparticles restrict glutamate production, inhibiting polarization towards the M2 phenotype. This resulted in an increased proportion of M1-TAMs, thereby improving the tumor immune microenvironment. Our study explores a nanotherapeutic strategy that enhances the biosafety of anti-glutamine metabolism therapy through folate targeting, effectively suppresses tumor cell proliferation, and enhances the anti-tumor immune response.

Keywords:  Ca(2+)-overloading; Folate targeting; Glutamine metabolism; Immune activation; Ovarian cancer

DOI:  https://doi.org/10.1016/j.jconrel.2024.12.073
J Cereb Blood Flow Metab. 2025 Jan 07. 271678X241310729

Glutamine metabolism is systemically different between primary and induced pluripotent stem cell-derived brain microvascular endothelial cells.

Callie M Weber, Bilal Moiz, Marzyeh Kheradmand, Arielle Scott, Claire Kettula, Brooke Wunderler, Viviana Alpízar Vargas, Alisa Morss Clyne.

  Human primary (hpBMEC) and induced pluripotent stem cell (iPSC)-derived brain microvascular endothelial-like cells (hiBMEC) are interchangeably used in blood-brain barrier models to study neurological diseases and drug delivery. Both hpBMEC and hiBMEC use glutamine as a source of carbon and nitrogen to produce metabolites and build proteins essential to cell function and communication. We used metabolomic, transcriptomic, and computational methods to examine how hpBMEC and hiBMEC metabolize glutamine, which may impact their utility in modeling the blood-brain barrier. We found that glutamine metabolism was systemically different between the two cell types. hpBMEC had a higher metabolic rate and produced more glutamate and GABA, while hiBMEC rerouted glutamine to produce more glutathione, fatty acids, and asparagine. Higher glutathione production in hiBMEC correlated with higher oxidative stress compared to hpBMEC. α-ketoglutarate (α-KG) supplementation increased glutamate secretion from hiBMEC to match that of hpBMEC; however, α-KG also decreased hiBMEC glycolytic rate. These fundamental metabolic differences between BMEC types may impact in vitro blood-brain barrier model function, particularly communication between BMEC and surrounding cells, and emphasize the importance of evaluating the metabolic impacts of iPSC-derived cells in disease models.

Keywords:  Blood-brain barrier; brain microvascular endothelial cells; glutamate metabolism; glutamine metabolism; metabolic flux analysis

DOI:  https://doi.org/10.1177/0271678X241310729
Immunol Lett. 2025 Jan 05. pii: S0165-2478(25)00006-9. [Epub ahead of print] 106974

Inhibition of Glutaminase 1 Reduces M1 Macrophage Polarization to Protect Against Monocrotaline-Induced Pulmonary Arterial Hypertension.

Xing Chen, Lixiang Li, Yan Deng, Juan Liao, Hui Meng, Limei Liang, Jie Hu, Dongwei Xie, Guizi Liang.

  (1) BACKGROUND: Metabolic abnormalities and immune inflammation are key elements within pathogenesis of pulmonary arterial hypertension (PAH). And in PAH patients, aberrant glutamine metabolism has been observed; however, the function of glutaminase 1 (GLS1) in macrophage is still unknown. So we aims to investigate GLS1's impact upon macrophages in PAH. (2) METHODS: We firstly constructed an monocrotaline (MCT)-induced PAH rat model. Briefly, the PAH rats were treated with the GLS1 inhibitor BPTES, and various index were evaluated, including hemodynamics, right ventricular function, pulmonary vascular remodeling, macrophage markers, and glutamine metabolism. After that, we polarized bone marrow-derived macrophages (BMDMs) into M1 phenotype and then subjected to BPTES intervention. Finally, we assessed macrophage phenotype, inflammatory markers, and glutamine metabolism indicators, along with the impact of BMDM supernatant on the behavior of pulmonary arterial smooth muscle cells (PASMCs). (3) RESULTS: : GLS1 was significantly upregulated in both PAH patients and rats. Treatment with the GLS1 inhibitor BPTES markedly improved pulmonary arterial pressure, right ventricular function, and pulmonary vascular remodeling in PAH rats, while inhibiting M1 macrophage polarization, NLRP3 activation, and the release of pro-inflammatory cytokines. This, in turn, alleviated the proliferation and migration of PASMCs induced by inflammatory stimuli. (4) CONCLUSION: : We propose that targeting GLS1 to reduce M1 macrophage polarization and inflammatory responses may represent a promising therapeutic approach for PAH.

Keywords:  Glutaminase 1; Glutamine Metabolism; Inflammation; Macrophage Polarization; Pulmonary Arterial Hypertension

DOI:  https://doi.org/10.1016/j.imlet.2025.106974
Front Oncol. 2024 ;14 1519046

The role of GOT1 in cancer metabolism.

Huan Peng, Huihong Dou, Sheng He, Yu-An Xie, Qinle Zhang, Jianqiu Zheng.

  GOT1, a cytoplasmic glutamic oxaloacetic transaminase, plays a critical role in various metabolic pathways essential for cellular homeostasis and dysregulated metabolism. Recent studies have highlighted the significant plasticity and roles of GOT1 in metabolic reprogramming through participating in both classical and non-classical glutamine metabolism, glycolytic metabolism, and other metabolic pathways. This review summarizes emerging insights on the metabolic roles of GOT1 in cancer cells and emphasizes the response of cancer cells to altered metabolism when the expression of GOT1 is altered. We review how cancer cells repurpose cell intrinsic metabolism and their flexibility when GOT1 is inhibited and delineate the molecular mechanisms of GOT1's interaction with specific oncogenes and regulators at multiple levels, including transcriptional and epigenetic regulation, which govern cellular growth and metabolism. These insights may provide new directions for cancer metabolism research and novel targets for cancer treatment.

Keywords:  GOT1; cancer; cell metabolism; metabolic reprogramming; therapeutic target

DOI:  https://doi.org/10.3389/fonc.2024.1519046
Front Immunol. 2024 ;15 1431112

Metabolic adaptation of myeloid cells in the glioblastoma microenvironment.

Nora Essakhi, Alexandre Bertucci, Nathalie Baeza-Kallee, Carole Colin, Rosario Lavignolle-Heguy, Paulina Garcia-Gonzalez, Rafael J Argüello, Aurélie Tchoghandjian, Emeline Tabouret.

  In recent decades, immunometabolism in cancers has emerged as an interesting target for treatment development. Indeed, the tumor microenvironment (TME) unique characteristics such as hypoxia and limitation of nutrients availability lead to a switch in metabolic pathways in both tumor and TME cells in order to support their adaptation and grow. Glioblastoma (GBM), the most frequent and aggressive primary brain tumor in adults, has been extensively studied in multiple aspects regarding its immune population, but research focused on immunometabolism remains limited. Here, we provide an overview of immunometabolism adaptation of myeloid cells in cancers with a specific focus on GBM and other brain tumors, before describing current therapeutic strategies targeting metabolic pathways. The main myeloid cells composing the GBM TME include tumor-associated macrophages (TAMs), which comprise both peripheral macrophages and local microglia, as well as myeloid-derived suppressor cells. The metabolic pathways involved in myeloid cell remodeling encompass the tricarboxylic acid cycle (TCA cycle), the lipid, glucose and amino acid metabolism and hypoxia. Developing treatments that target these metabolic pathways in tumor growth and its TME is a promising and increasing field. It includes both drug-repurposing and the development of innovative metabolic therapies. We finally provide an overview of all clinical trials in neuro-oncology involving treatments modifying cell metabolism and provide the preclinical rationale for both drugs already evaluated within clinical trials and potential candidates for future trials.

Keywords:  TCA cycle; glioblastoma; glycolysis; lipid metabolism; metabolism; myeloid cells

DOI:  https://doi.org/10.3389/fimmu.2024.1431112
Biomedicines. 2024 Nov 25. pii: 2684. [Epub ahead of print]12(12):

Metabolic Crossroad Between Macrophages and Cancer Cells: Overview of Hepatocellular Carcinoma.

Anna Santarsiero, Paolo Convertini, Dominga Iacobazzi, Vittoria Infantino, Simona Todisco.

  The metabolic interplay between macrophages and cancer cells mirrors the plasticity of both kinds of cells, which adapt to the microenvironment by sustaining cell growth and proliferation. In this way, cancer cells induce macrophage polarization, and, on the other hand, tumor-associated macrophages (TAMs) contribute to the survival of cancer cells. In a simplified manner, macrophages can assume two opposite subtypes: M1, pro-inflammatory and anti-tumor phenotype, and M2, anti-inflammatory and protumor phenotype. How do cancer cells induce macrophage polarization? Any actor involved in tumor growth, including the mitochondria, releases molecules into the tumor microenvironment (TME) that trigger a subtype transition. These metabolic changes are the primary cause of this polarization. Hepatocellular carcinoma (HCC), the prevalent type of liver primary tumor, is characterized by cells with extensive metabolic adaptions due to high flexibility in different environmental conditions. This review focuses on the main metabolic features of M1 and M2 macrophages and HCC cells underlying their metabolic behavior in response to TME.

Keywords:  cancer cells; cellular signals; hepatocellular carcinoma; macrophages; metabolic reprogramming; mitochondria

DOI:  https://doi.org/10.3390/biomedicines12122684
Int J Mol Sci. 2024 Dec 10. pii: 13242. [Epub ahead of print]25(24):

Altered Cellular Metabolism Is a Consequence of Loss of the Ataxia-Linked Protein Sacsin.

Laura Perna, Grace Salsbury, Mohammed Dushti, Christopher J Smith, Valle Morales, Katiuscia Bianchi, Gabor Czibik, J Paul Chapple.

  Mitochondrial dysfunction is implicated in the pathogenesis of the neurological condition autosomal recessive spastic ataxia of Charlevoix-Saguenay (ARSACS), yet precisely how the mitochondrial metabolism is affected is unknown. Thus, to better understand changes in the mitochondrial metabolism caused by loss of the sacsin protein (encoded by the SACS gene, which is mutated in ARSACS), we performed mass spectrometry-based tracer analysis, with both glucose- and glutamine-traced carbon. Comparing the metabolite profiles between wild-type and sacsin-knockout cell lines revealed increased reliance on aerobic glycolysis in sacsin-deficient cells, as evidenced by the increase in lactate and reduction of glucose. Moreover, sacsin knockout cells differentiated towards a neuronal phenotype had increased levels of tricarboxylic acid cycle metabolites relative to the controls. We also observed disruption in the glutaminolysis pathway in differentiated and undifferentiated cells in the absence of sacsin. In conclusion, this work demonstrates consequences for cellular metabolism associated with a loss of sacsin, which may be relevant to ARSACS.

Keywords:  ARSACS; aerobic glycolysis; metabolism; mitochondria; sacsin

DOI:  https://doi.org/10.3390/ijms252413242
Blood. 2024 Dec 27. pii: blood.2024025245. [Epub ahead of print]

α-Ketoglutarate dehydrogenase is a therapeutic vulnerability in acute myeloid leukemia.

Scott Evan Millman, Almudena Chaves-Perez, Sudha Janaki-Raman, Yu-Jui Ho, John P Morris Iv, Varun Narendra, Chi-Chao Chen, Benjamin T Jackson, Jossie J Yashinskie, Riccardo Mezzadra, Tessa I Devine, Valentin J A Barthet, Michelle Saoi, Timour Baslan, Sha Tian, Zohar Sachs, Lydia Ws Finley, Justin R Cross, Scott W Lowe.

Perturbations in intermediary metabolism contribute to the pathogenesis of acute myeloid leukemia (AML) and can produce therapeutically actionable dependencies. Here, we probed whether alpha-ketoglutarate (aKG) metabolism represents a specific vulnerability in AML. Using functional genomics, metabolomics, and mouse models, we identified the aKG dehydrogenase complex, which catalyzes the conversion of aKG to succinyl CoA, as a molecular dependency across multiple models of adverse-risk AML. Inhibition of 2-oxoglutarate dehydrogenase (OGDH), the E1 subunit of the aKG dehydrogenase complex, impaired AML progression and drove differentiation. Mechanistically, hindrance of aKG flux through the tricarboxylic acid (TCA) cycle resulted in rapid exhaustion of aspartate pools and blockade of de novo nucleotide biosynthesis, while cellular bioenergetics was largely preserved. Additionally, increased aKG levels following OGDH inhibition impacted the biosynthesis of other critical amino acids. Thus, this work has identified a previously undescribed, functional link between certain TCA cycle components and nucleotide biosynthesis enzymes across AML. This metabolic node may serve as a cancer-specific vulnerability amenable to therapeutic targeting in AML and perhaps in other cancers with similar metabolic wiring.

DOI: https://doi.org/10.1182/blood.2024025245
Mol Cancer. 2025 Jan 09. 24(1): 7

Tumor metabolic regulators: key drivers of metabolic reprogramming and the promising targets in cancer therapy.

Kun Huang, Ying Han, Yihong Chen, Hong Shen, Shan Zeng, Changjing Cai.

  Metabolic reprogramming within the tumor microenvironment (TME) is a hallmark of cancer and a crucial determinant of tumor progression. Research indicates that various metabolic regulators form a metabolic network in the TME and interact with immune cells, coordinating the tumor immune response. Metabolic dysregulation creates an immunosuppressive TME, impairing the antitumor immune response. In this review, we discuss how metabolic regulators affect the tumor cell and the crosstalk of TME. We also summarize recent clinical trials involving metabolic regulators and the challenges of metabolism-based tumor therapies in clinical translation. In a word, our review distills key regulatory factors and their mechanisms of action from the complex reprogramming of tumor metabolism, identified as tumor metabolic regulators. These regulators provide a theoretical basis and research direction for the development of new strategies and targets in cancer therapy based on tumor metabolic reprogramming.

Keywords:  Cancer therapy; Metabolic regulators; Metabolic reprogramming; TME

DOI:  https://doi.org/10.1186/s12943-024-02205-6
Front Nutr. 2024 ;11 1414367

Impact of a glutamine-enriched peptide formula on gastrointestinal toxicity and on the interruption of oncologic treatment in patients with adenocarcinoma of the rectum.

Bárbara Gabriela Salas-Salas, Laura Ferrera-Alayón, Alicia Calleja-Fernández, Rodolfo Chicas-Sett, Eva Nogués-Ramia, Juan Zafra-Martín, Marta Lloret.

   Background: Patients with rectal cancer may develop gastrointestinal toxicity associated with chemo-radiotherapeutic treatment that conditions their clinical, functional, and nutritional evolution. The aim of the study was to evaluate the efficacy of nutritional supplementation with a glutamine-enriched peptide diet (PD) compared to exclusive dietary advice (DA) on gastrointestinal toxicity, interruption of oncologic treatment, and nutritional evolution in patients with rectal cancer undergoing neoadjuvant treatment.
Methods: Prospective cohort study with two groups. Patients with rectal cancer in treatment with neoadjuvant chemo-radiotherapy were recruited. One group of patients received nutritional supplementation with PD, and another group received DA exclusively, from the beginning of radiotherapy until the time of surgery. Intestinal toxicity was evaluated with the CTCAE 5.0 scale, functionality with the ECOG scale and nutritional status with GLIM criteria.
Results: Fifty-four patients were initially selected, although 51 were finally enrolled: 25 in the PD group and 26 in the DA group. There was a reduction in the risk of diarrhea in the PD group midway through radiotherapy treatment [RR of 0.218 (95% CI = 0.052-0.923)] and at the end of treatment [RR of 0.103 (95% CI = 0.020-0.537)], as well as a reduction in the risk of developing mucositis at the end of treatment [RR of 0.405 (95% CI = 0.280-0.584)]. The use of a PD also decreased treatment interruptions with radiotherapy in stage III patients (0 vs. 15.8%, p = 0.049) and in malnourished patients (0 vs. 18.2%, p = 0.040).
Conclusion: The glutamine-enriched peptide diet had a protective effect on the development of diarrhea and mucositis associated with chemo-radiotherapeutic treatment in patients with colorectal cancer under neoadjuvant treatment, as well as the interruption of radiotherapeutic treatment.

Keywords:  glutamine; oral nutritional supplement; peptide diet; radiotherapy; rectal cancer

DOI:  https://doi.org/10.3389/fnut.2024.1414367
Adv Sci (Weinh). 2025 Jan 05. e2406220

RTN4IP1 Contributes to ESCC via Regulation of Amino Acid Transporters.

Huifang Wei, Dengyun Zhao, Yafei Zhi, Qiong Wu, Jing Ma, Jialuo Xu, Tingting Liu, Jing Zhang, Penglei Wang, Yamei Hu, Xinyu He, Fangqin Guo, Ming Jiang, Dandan Zhang, Wenna Nie, Ran Yang, Tongjin Zhao, Zigang Dong, Kangdong Liu.

  Esophageal squamous cell carcinoma (ESCC) accounts for about 90% of esophageal cancer cases. The lack of effective therapeutic targets makes it difficult to improve the overall survival of patients with ESCC. Reticulon 4 Interacting Protein 1 (RTN4IP1) is a novel mitochondrial oxidoreductase. Here, a notable upregulation of RTN4IP1 is demonstrated, which is associated with poor survival in patients with ESCC. RTN4IP1 depletion impairs cell proliferation and induces apoptosis of ESCC cells. Furthermore, c-Myc regulates RTN4IP1 expression via iron regulatory protein 2 (IRP2) at the post-transcriptional level. Mechanistically, RTN4IP1 mRNA harbors functional iron-responsive elements (IREs) in the 3' UTR, which can be targeted by IRP2, resulting in increased mRNA stability. Finally, RTN4IP1 depletion abrogates amino acid uptake and induces amino acid starvation via downregulation of the amino acid transporters SLC1A5, SLC3A2, and SLC7A5, indicating a possible pathway through which RTN4IP1 contributes to ESCC carcinogenesis and progression. In vivo studies using cell-derived xenograft and patient-derived xenograft mouse models as well as a 4-nitroquinoline 1-oxide-induced ESCC model in esophageal-specific Rtn4ip1 knockout mice demonstrate the essential role of RTN4IP1 in ESCC development. Thus, RTN4IP1 emerges as a key cancer-promoting protein in ESCC, suggesting therapeutic RTN4IP1 suppression as a promising strategy for ESCC treatment.

Keywords:  Amino acid transporters; ESCC; Iron regulatory proteins; Iron responsive element; RTN4IP1; c‐Myc

DOI:  https://doi.org/10.1002/advs.202406220
Dis Esophagus. 2025 Jan 07. pii: doae121. [Epub ahead of print]38(1):

HMB/Arg/Gln may improve short-term outcomes after esophagectomy in patients with thoracic esophageal cancer.

Katsushi Takebayashi, Sachiko Kaida, Reiko Otake, Asuka Fukuo, Toru Miyake, Masatsugu Kojima, Soichiro Tani, Hiromitsu Maehira, Haruki Mori, Hajime Ishikawa, Masaji Tani.

   BACKGROUND: The wound healing effects of a specialized amino acid supplement containing calcium beta-hydroxy-beta-methylbutyrate, L-arginine, and L-glutamine (HMB/Arg/Gln) have been reported. This study aimed to investigate the effectiveness of HMB/Arg/Gln in the perioperative management of patients with thoracic esophageal cancer.
METHODS: This retrospective cohort study included 131 patients who underwent esophagectomy for thoracic esophageal cancer between January 2016 and November 2023. Postoperative infectious complications (PICs) were compared between patients who received HMB/Arg/Gln for 7 days before surgery (n = 95) and those who did not (control group, n = 36).
RESULTS: Among the 111 male and 20 female patients (median age 68 years, range 38-84 years), stage I disease was found in 37 patients, stage II in 26, stage III in 61, and stage IVa in 7. Of the 131 patients, 36 (27.5%) had PICs, with PICs occurring in 20 (21%) of the HMB/Arg/Gln group and 16 (44.4%) of the control group. The PIC rate was significantly lower in the HMB/Arg/Gln than in the control group (p = 0.007). Propensity score matching analysis showed lower rates of anastomotic leakage (5.5% vs. 22.2%; p = 0.04) and Clavien-Dindo grade III or higher PICs (5.5% vs. 27.8%; p = 0.011) in the HMB/Arg/Gln than in the control group. The healing time for anastomotic leakage was shorter in the HMB/Arg/Gln (18 days, range 7-25 days) than in the control group (25 days, range 21-56 days) (p = 0.033).
CONCLUSIONS: HMB/Arg/Gln supplementation was associated with reduced risk of anastomotic leakage and PIC severity following esophagectomy.

Keywords:  Abound; Anastomotic leakage; Esophageal cancer; Esophagectomy; Hmb/arg/gln

DOI:  https://doi.org/10.1093/dote/doae121
Biomedicines. 2024 Dec 19. pii: 2899. [Epub ahead of print]12(12):

Metabolomic Profiling of Oral Potentially Malignant Disorders and Its Clinical Values.

Nur Fatinazwa Mohd Faizal, Vui King Vincent-Chong, Anand Ramanathan, Ian C Paterson, Lee Peng Karen-Ng, Zuraiza Mohamad Zaini.

  Oral potentially malignant disorders (OPMD) are a group of lesions carrying the risk of developing into cancer. The gold standard to predict which lesions are more likely to undergo malignant transformation is the presence of dysplasia histologically. However, not all dysplastic lesions progress, and non-dysplastic lesions may also undergo malignant transformation. Oral carcinogenesis is a complex molecular process that involves somatic alterations and the deregulation of transcriptions, protein expression, and metabolite levels. Metabolomics, which is the scientific study of metabolites, has emerged as a promising high-throughput approach to investigate the metabolic changes of small molecules in biological pathways. In this review, we summarize the data relating to the metabolomic profiling of OPMDs, which will help elucidate the complex process of oral carcinogenesis. Furthermore, we identify that among all metabolites, citrate, pyruvate, and glutamate may serve as potential biomarkers for oral leukoplakia (OLK). Notably, metformin and gluconate have been shown to target glutamate and citrate, respectively, in cancer cells. Based on these findings, we propose that targeting these metabolites in patients with OPMD could be a promising therapeutic strategy to mitigate OPMD progression and potentially reduce the risk of malignant transformation. We also discuss the limitations and future directions of metabolomics in OPMD. Understanding these important metabolites is crucial for early detection and monitoring of oral cancer progression.

Keywords:  biomarkers; metabolomics; oral potentially malignant disorder; oral squamous cell carcinoma

DOI:  https://doi.org/10.3390/biomedicines12122899
mBio. 2025 Jan 08. e0354624

Genetic and biochemical characterization of a radical SAM enzyme required for post-translational glutamine methylation of methyl-coenzyme M reductase.

Roy J Rodriguez Carrero, Cody T Lloyd, Janhavi Borkar, Shounak Nath, Liviu M Mirica, Satish Nair, Squire J Booker, William Metcalf.

  Methyl-coenzyme M reductase (MCR), the key catalyst in the anoxic production and consumption of methane, contains an unusual 2-methylglutamine residue within its active site. In vitro data show that a B12-dependent radical SAM (rSAM) enzyme, designated MgmA, is responsible for this post-translational modification (PTM). Here, we show that two different MgmA homologs are able to methylate MCR in vivo when expressed in Methanosarcina acetivorans, an organism that does not normally possess this PTM. M. acetivorans strains expressing MgmA showed small, but significant, reductions in growth rates and yields on methylotrophic substrates. Structural characterization of the Ni(II) form of Gln-methylated M. acetivorans MCR revealed no significant differences in the protein fold between the modified and unmodified enzyme; however, the purified enzyme contained the heterodisulfide reaction product, as opposed to the free cofactors found in eight prior M. acetivorans MCR structures, suggesting that substrate/product binding is altered in the modified enzyme. Structural characterization of MgmA revealed a fold similar to other B12-dependent rSAMs, with a wide active site cleft capable of binding an McrA peptide in an extended, linear conformation.IMPORTANCEMethane plays a key role in the global carbon cycle and is an important driver of climate change. Because MCR is responsible for nearly all biological methane production and most anoxic methane consumption, it plays a major role in setting the atmospheric levels of this important greenhouse gas. Thus, a detailed understanding of this enzyme is critical for the development of methane mitigation strategies.

Keywords:  Methanosarcina; archaea; methanogenesis; methyl-coenzyme M reductase; post-translational modification

DOI:  https://doi.org/10.1128/mbio.03546-24