FSMP-19. SEX DIFFERENCES IN REDOX REGULATION UNDERLIE GLUTAMINE DEPENDENCY IN MALE GLIOBLASTOMA

Abstract Glioblastoma (GBM) is the most aggressive primary brain tumor in adults. GBM occurs more commonly in males but female patients survive significantly longer. Understanding the molecular mechanisms underlying this clinical sex disparity could support novel treatment strategies to improve outcomes for GBM patients. In this regard, we found that male and female GBM patient tissues differ in their metabolite profiles and that male GBM exhibit a higher abundance of amino acid metabolites. We confirmed these findings in a murine model of GBM. Furthermore, we found that male GBM cells are more sensitive to amino acid deprivation. This male-specific dependency on amino acids is almost entirely driven by amino acids involved in reactive oxygen species (ROS) regulation and glutathione synthesis. We found that male GBM cells are more sensitive to depletion of glutathione, which resulted in a significant increase in ROS and cell death in male GBM cells. Moreover, assays of glutathione oxidation demonstrated that male GBM cells exist in a chronically oxidized state. GLS1 mediates the conversion from glutamine to glutamate, a crucial component of glutathione. We found that male GBM cells are more sensitive to GLS1 inhibition with the clinical inhibitor CB-839. This correlated with significantly increased ROS and glutathione levels as well as significantly decreased TCA cycle metabolites in male GBM. Lastly, we found that the TCA cycle metabolite α-ketoglutarate rescues the effects of CB-839 in male GBM cells. Together, these data suggest that (1) male and female GBM differ in their amino acid requirements, (2) male GBM are more dependent on glutathione to regulate ROS levels, and (3) male GBM increase glutathione synthesis at the expense of TCA cycle metabolites upon GLS1 inhibition, suggesting an increased susceptibility to drugs targeting the glutamate/glutathione axis in male GBM. Our data underline the importance of considering sex in metabolic targeting approaches.

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TAMI-37. SEX DIFFERENCES IN REDOX STATE UNDERLIE GLUTAMINE DEPENDENCY IN MALE GLIOBLASTOMA

Neuro-Oncology ◽

10.1093/neuonc/noaa215.925 ◽

2020 ◽

Vol 22 (Supplement_2) ◽

pp. ii221-ii221

Author(s):

Jasmin Sponagel ◽

Shanshan Zhang ◽

Jill Jones ◽

Prakash Chinnaiyan ◽

Joshua Rubin ◽

...

Keyword(s):

Amino Acids ◽

Sex Differences ◽

Amino Acid ◽

Redox State ◽

Molecular Mechanisms ◽

Treatment Strategies ◽

Tca Cycle ◽

Primary Brain Tumor ◽

Male And Female ◽

Amino Acid Requirements

Abstract Glioblastoma (GBM) is the most aggressive primary brain tumor in adults. GBM occurs more commonly in males but female patients survive significantly longer. Understanding the molecular mechanisms underlying this clinical sex disparity could support novel treatment strategies to improve outcomes for GBM patients. In this regard, we found that male and female GBM patient tissues differ in their metabolite profiles and that male GBM exhibit a higher abundance of amino acid metabolites. We confirmed these findings in a murine model of GBM. Furthermore, we found that male GBM cells are more sensitive to amino acid deprivation. This male-specific dependency on amino acids is almost entirely driven by amino acids involved in the synthesis of the antioxidant glutathione. Glutaminase 1 (GLS1) mediates the conversion from glutamine to glutamate, a crucial component of glutathione. We found that male GBM cells are more sensitive to GLS1 inhibition with the clinical inhibitor CB-839. This correlated with significantly increased reactive oxygen species (ROS) in male GBM. We further confirmed sex differences in redox state through pharmacological depletion of glutathione, which resulted in a significant increase in ROS and cell death in male GBM cells. Moreover, assays of glutathione oxidation demonstrated that male GBM cells exist in a chronically oxidized state. Finally, we found that mitochondrial structure and function, including TCA cycle flux, NADH levels, and antioxidant activity, differ between male and female GBM cells. Together, these data suggest that (1) male and female GBM differ in their amino acid requirements, (2) male GBM are more dependent on glutamine to regulate ROS levels, and (3) sex differences in mitochondrial physiology may result in ROS accumulation and increased susceptibility to drugs targeting the redox state in male GBM. Our data reveal novel metabolic targets for GBM and underline the importance of considering sex in metabolic targeting approaches.

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CBMT-45. SEX-SPECIFIC METABOLIC ADAPTIONS IN GLIOBLASTOMA

Neuro-Oncology ◽

10.1093/neuonc/noz175.167 ◽

2019 ◽

Vol 21 (Supplement_6) ◽

pp. vi42-vi43

Author(s):

Jasmin Sponagel ◽

Shanshan Zhang ◽

Prakash Chinnaiyan ◽

Joshua Rubin ◽

Joseph Ippolito

Keyword(s):

Sex Differences ◽

Sexual Dimorphism ◽

Molecular Mechanisms ◽

Treatment Strategies ◽

Tca Cycle ◽

Metabolic Reprogramming ◽

Mitochondrial Activity ◽

Male And Female ◽

Glutamine Deprivation ◽

Novel Treatment Strategies

Abstract Glioblastoma (GBM) is the most common and aggressive brain tumor in adults. GBM occurs more commonly in males, but female patients survive significantly longer. Understanding the molecular mechanisms that underlie those sex differences could support novel treatment strategies. In this regard, we found that male and female GBM patient samples differ in their metabolite abundance and that male patients exhibit a significantly higher abundance of TCA cycle metabolites. We confirmed those findings in a murine model of GBM, which has previously yielded important insights into sexual dimorphism in GBM. Strikingly, sex differences in TCA cycle flux were entirely driven by glutamine flux, not glucose flux, suggesting a sex-specific role for glutamine in GBM. Metabolic manipulation through glutamine deprivation resulted in a greater growth inhibition in male GBM cells. Glutamine itself can be utilized for anabolic reactions or it can be converted to glutamate by glutaminase. Only male GBM cells were sensitive to pharmacological glutaminase inhibition with BPTES or CB-839, suggesting that male GBM cells are glutamate dependent while female GBM cells are not. Concordantly, we found significantly higher glutaminase levels in male GBM cells. Furthermore, we found that numerous metabolites (including NADH, ATP, and glutathione) involved in cellular processes downstream of glutamate were more abundant in male GBM cells. In contrast, female GBM cells were resistant to low glutamine conditions and glutaminase inhibitors unless glutamine-synthase activity was disrupted, suggesting that glutamine synthesis might play a more prominent role in female GBM. Together, these data indicate that male and female GBM differ in their metabolic adaptions. Male GBM utilize glutamate to fuel the TCA cycle and mitochondrial activity while female GBM synthesize and utilize glutamine itself. This sexual dimorphism in metabolic reprogramming reveals novel sex specific metabolic targets for GBM and underlines the importance of considering sex in metabolic targeting approaches.

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Reevaluation of digestible amino acid requirements of male and female broilers based on different ideal amino acids ratios in starter period

Livestock Science ◽

10.1016/j.livsci.2012.04.016 ◽

2012 ◽

Vol 147 (1-3) ◽

pp. 154-158 ◽

Cited By ~ 2

Author(s):

E. Salehifar ◽

M. Shivazad ◽

F. Foroudi ◽

M. Chamani ◽

R. Bahari Kashani

Keyword(s):

Amino Acids ◽

Amino Acid ◽

Male And Female ◽

Amino Acid Requirements

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Simultaneous Identification and Evaluation of Amino Acid Profiles of the Male and Female Innards of Neopetrolisthes maculatus

International Letters of Natural Sciences ◽

10.18052/www.scipress.com/ilns.75.13 ◽

2019 ◽

Vol 75 ◽

pp. 13-26 ◽

Cited By ~ 2

Author(s):

Emmanuel Ilesanmi Adeyeye

Keyword(s):

Amino Acids ◽

Amino Acid ◽

Quality Parameters ◽

Total Amino Acid ◽

Male And Female ◽

Hen’S Egg ◽

Two Samples ◽

Amino Acid Requirements ◽

Amino Acid Profiles ◽

Simultaneous Identification

This article reports the amino acid profiles of the innards of the male and female dry samples ofN. maculatuscollected from the Atlantic Ocean at Orimedu beach in Ibeju-Lekki, Lagos, Nigeria. The analytical results showed high values of amino acids being observed in both heterosexual samples (g 100g-1protein): 8.17-8.32 (Leu), 8.35-10.3 (Asp), 17.6-18.2 (Glu) and 7.76-9.55 (Arg) with total amino acid values being greater in female innards (97.6g100g-1) than the male innards (95.5g 100g-1). These quality parameters were instructive of the quality of the amino acids in the innards ofN. maculatus: P-PER1, (2.83-3.01), P-PER2(2.89-2.96), EAAI (88.7-89.0), BV (85.0-85.5), Lys/Trp (L/T) (3.00-5.01), Met/Trp (M/T) (1.78-3.50) and Phe/Tyr (1.04-1.65). ThepIvalues were close at 5.46-5.57. In the amino acid groups (classes), the following trend was observed: class I > IV >V > VI > II > III > VII. For the amino acid scores: serine (0.487-0.511) was limiting in both samples on the total hen’s egg scoring pattern; in provisional scoring pattern, Lys was limiting in both samples with values of 0.820-0.889 and in the pre-school amino acid requirements, Lys was also limiting at 0.778-0.843. In the statistical analyses total amino acid profiles as well as egg scores were significantly different between the two samples whereas quality scores in pre-school amino acid requirements and provisional amino acid scoring pattern were both not significantly different between the two samples all at r=0.01. Among the EAAs, six out of nine (66.7%) were more concentrated in the male innards and three of nine (33.3%) were more concentrated in the female. Thus the overall summary showed the male innards amino acids were of better quality than in the female as shown: male innards EEA = 46.1 g100g-1and 46.0 g100g-1in the female with corresponding TNEAA of 49.3g 100g-1and 51.6g 100g-1respectively.

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Effect of Intraduodenal Starch Infusion on Net Portal Absorption of Amino Acids in Growing steers Fed Lucerne

Proceedings of the British Society of Animal Production (1972) ◽

10.1017/s0308229600025800 ◽

1994 ◽

Vol 1994 ◽

pp. 28-28

Author(s):

C.J. Seal ◽

D.S. Parker ◽

J.C. MacRae ◽

G.E. Lobley

Keyword(s):

Amino Acids ◽

Amino Acid ◽

Gastrointestinal Tract ◽

Protein Turnover ◽

Portal Blood ◽

Intestinal Lumen ◽

Short Term ◽

Net Uptake ◽

Amino Acid Requirements ◽

Glucose Availability

Amino acid requirements for energy metabolism and protein turnover within the gastrointestinal tract are substantial and may be met from luminal and arterial pools of amino acids. Several studies have demonstrated that the quantity of amino acids appearing in the portal blood does not balance apparent disappearance from the intestinal lumen and that changing diet or the availability of energy-yielding substrates to the gut tissues may influence the uptake of amino acids into the portal blood (Seal & Reynolds, 1993). For example, increased net absorption of amino acids was observed in animals receiving exogenous intraruminal propionate (Seal & Parker, 1991) and this was accompanied by changes in glucose utilisation by the gut tissues. In contrast, there was no apparent change in net uptake of [l-13C]-leucine into the portal vein of sheep receiving short term intraduodenal infusions of glucose (Piccioli Cappelli et al, 1993). This experiment was designed to further investigate the effects on amino acid absorption of changing glucose availability to the gut with short term (seven hours) or prolonged (three days) exposure to starch infused directly into the duodenum.

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Amino acids in blood plasma and tissues of rats following glucose force-feeding

Canadian Journal of Biochemistry ◽

10.1139/o69-049 ◽

1969 ◽

Vol 47 (3) ◽

pp. 323-327 ◽

Cited By ~ 4

Author(s):

J. E. Knipfel ◽

H. G. Botting ◽

F. J. Noel ◽

J. M. McLaughlan

Keyword(s):

Amino Acids ◽

Amino Acid ◽

Blood Plasma ◽

Protein Composition ◽

Tissue Uptake ◽

Body Protein ◽

Glucose Administration ◽

Force Feeding ◽

Amino Acid Requirements ◽

Concentration Changes

Changes in plasma amino acid (PAA) concentrations effected by force-feeding glucose to rats were studied in two experiments. Attempts were made to relate PAA concentration changes to amino acid requirements, previous diet, time after feeding glucose, and composition of several body proteins. Distribution of 14C-lysine between blood and tissues was examined in an additional rat experiment. Previous diet did not affect the relative quantities of amino acids removed from plasma (PAA removal pattern) after glucose force-feeding. Minimal PAA concentrations occurred by 40 min after glucose administration. The PAA removal pattern was not distinctly related to either amino acid requirements or to any particular body protein composition. Results of administering 14C-lysine simultaneously with glucose indicated that decreased plasma 14C-lysine levels were caused by increased tissue uptake of 14C, likely mediated by insulin. Muscle acted as the major recipient of 14C from plasma, with liver a lesser and more dynamic reservoir of 14C accumulation. Work is continuing to further clarify the significance of the PAA removal pattern, caused by the force-feeding of glucose.

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Amino Acid Characteristics of Nigerian Local Cheese (‘Wara’)

10.47363/jftns/2021(3)116 ◽

2021 ◽

pp. 1-8

Author(s):

Adeyeye EI ◽

◽

Idowu OT ◽

Keyword(s):

Amino Acids ◽

Amino Acid ◽

Essential Amino Acid ◽

Crude Protein ◽

Milk Protein ◽

Quality Parameters ◽

Cow Milk ◽

Amino Acid Requirements ◽

Excellent Source ◽

Better Than

This article reports the amino acid composition of the Nigerian local cheese called ‘wara’. ‘Wara’ is made by boiling cow milk with some added coagulant to cuddle the milk protein resulting in coagulated milk protein and whey. ‘Wara’ used to be an excellent source of nutrients such as proteins, fats, minerals and vitamins. Samples were purchased in Ado-Ekiti, Nigeria. Amino acid values were high (g/100g crude protein) in Leu, Asp, Glu, Pro, Phe, Arg with total value of 97.7. The quality parameters of the amino acids were: TEAA (42.6g/100g and 43.6%) whereas TNEAA (55.1g/100g and 56.4%); TArAA (12.8g/100g and 13.1%); TBAA (14.2g/100g and 14.5%); TSAA (3.10g/100g and 3.17%); %Cys in TSAA (51.4); Leu/Ile ratio (1.74); P-PER1 (2.65); P-PER2 (2.48); P-PER3 (2.41); EAAI1 (soybean standard) (1.29) and EAAI2 (egg standard) (99.9); BV (97.2) and Lys/Trp ratio (3.62). The statistical analysis of TEAA/TNEAA at r=0.01 was not significantly different. On the amino acid scores, Met was limiting (0.459) at egg comparison, Lys was limiting at both FAO/WHO [24] and preschool EAA requirements with respective values of 0.966 and 0.97. Estimates of essential amino acid requirements at ages 10-12 years (mg/kg/day) showed the ‘wara’ sample to be better than the standard by 3.72-330% with Lys (3.72%) being least better and Trp (330%) being most. The results showed that ‘wara’ is protein-condensed which can be eaten as raw cheese, flavoured snack, sandwich filling or fried cake.

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Multiple Transmembrane Amino Acid Requirements Suggest a Highly Specific Interaction between the Bovine Papillomavirus E5 Oncoprotein and the Platelet-Derived Growth Factor Beta Receptor

Journal of Virology ◽

10.1128/jvi.76.16.7976-7986.2002 ◽

2002 ◽

Vol 76 (16) ◽

pp. 7976-7986 ◽

Cited By ~ 17

Author(s):

Valerie M. Nappi ◽

Lisa M. Petti

Keyword(s):

Amino Acids ◽

Amino Acid ◽

Growth Factor ◽

Transmembrane Domain ◽

Specific Interaction ◽

Platelet Derived Growth Factor ◽

Helical Conformation ◽

Bovine Papillomavirus ◽

E5 Protein ◽

Amino Acid Requirements

ABSTRACT The bovine papillomavirus E5 protein activates the cellular platelet-derived growth factor β receptor (PDGFβR) tyrosine kinase in a ligand-independent manner. Evidence suggests that the small transmembrane E5 protein homodimerizes and physically interacts with the transmembrane domain of the PDGFβR, thereby inducing constitutive dimerization and activation of this receptor. Amino acids in the receptor previously found to be required for the PDGFβR-E5 interaction are a transmembrane Thr513 and a juxtamembrane Lys499. Here, we sought to determine if these are the only two receptor amino acids required for an interaction with the E5 protein. Substitution of large portions of the PDGFβR transmembrane domain indicated that additional amino acids in both the amino and carboxyl halves of the receptor transmembrane domain are required for a productive interaction with the E5 protein. Indeed, individual amino acid substitutions in the receptor transmembrane domain identified roles for the extracellular proximal transmembrane residues in the interaction. These data suggest that multiple amino acids within the transmembrane domain of the PDGFβR are required for a stable interaction with the E5 protein. These may be involved in direct protein-protein contacts or may support the proper transmembrane alpha-helical conformation for optimal positioning of the primary amino acid requirements.

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Plasma essential amino acids concentrations of early lactating Holstein dairy cows fed diet containing raw or roasted Iranian soybean

Proceedings of the British Society of Animal Science ◽

10.1017/s1752756200020858 ◽

2007 ◽

Vol 2007 ◽

pp. 182-182

Author(s):

Forouzan Tabatabaie ◽

Hassan Fathi ◽

Mohsen Danesh

Keyword(s):

Amino Acids ◽

Amino Acid ◽

Dairy Cows ◽

Physical Method ◽

Essential Amino Acids ◽

High Energy ◽

Early Lactation ◽

High Amino Acid ◽

Amino Acid Requirements ◽

Physical Treatments

Whole soybean has 40-42 percent CP and used as high energy-protein supplement for early lactation dairy cows. However, the protein is highly degradable, so small amounts of amino acids can be reached to small intestine to meet high amino acid requirements of early lactating cows. Therefore, various chemical and physical treatments have been suggested to decrease ruminal protein degradability of soybeans. The practical use and application of any one method to lower ruminal feed degradability is dependent not only on its efficacy but also on its cost effectiveness, safety and ease of application. For these reasons, heat treatment is the most commonly used physical method (Plegge et al., 1985). The purpose of this study was to determine how roasting of soybeans affect plasma essential amino acid concentrations in early lactation cows.

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P207 Synergetic effect of amino acid and ketone metabolism underlies empagliflozin-mediated cardioprotection in the type 2 diabetic heart

European Heart Journal ◽

10.1093/ehjci/ehz872.077 ◽

2020 ◽

Vol 41 (Supplement_1) ◽

Author(s):

H Kouzu ◽

H Oshima ◽

T Miki ◽

A Kuno ◽

T Sato ◽

...

Keyword(s):

Amino Acid ◽

Survival Rate ◽

Molecular Mechanisms ◽

Synergetic Effect ◽

Tca Cycle ◽

Oxidative Capacity ◽

Metabolome Analysis ◽

Coa Transferase ◽

The Tca Cycle

Abstract Funding Acknowledgements Boehringer Ingelheim Background Although emerging evidence has indicated that sodium glucose cotransporter 2 (SGLT2) inhibitors restore impaired cardiac energetics in type 2 diabetes mellitus (T2DM), the underlying molecular mechanisms have yet to be established. Augmented utilization of ketone is one proposed hypothesis, but depletion of succinyl-CoA triggered by the conversion of ketone back to acetyl-CoA by SCOT (succinyl-CoA:3-oxoacid CoA transferase) may hamper oxidative capacity of the tricarboxylic acid (TCA) cycle, which also requires succinyl-CoA. The recent finding that empagliflozin augments systemic amino acid metabolism in patients with T2DM led us to hypothesize that the anaplerotic effect of amino acid on the TCA cycle complements ketone oxidation. Methods and Results Myocardial infarction (MI) was induced in T2DM rats (OLETF) and control rats (LETO). Survival rate at 48 hours after MI was significantly lower in OLETF than in LETO (40% vs 84%), and empagliflozin treatment (10 mg/kg/day, 14 days) before MI improved the survival rate in OLETF to 70%. Metabolome analysis was performed using heart tissues from the non-infarct region 12 hours after MI. Using principal component analysis, data from 92 metabolites that were detected were compressed into 2 dimensions, and the first component (PC1) clearly separated empagliflozin-treated OLETF from non-treated LETO and OLETF. Analysis of factor loading of each metabolite for PC1 revealed that branched chain amino acids leucine, isoleucine and valine, the latter two of which can be oxidized to succynyl-CoA, and β-hydroxybutyrate were the top four metabolites that characterized empagliflozin treatment. Furthermore, in comparison to LETO, OLETF treated with empagliflozin showed 50% higher levels of glutamine and glutamate, both of which can replenish the TCA cycle at the level of α-ketoglutarate. In OLETF, empagliflozin significantly increased the TCA cycle intermediates citrate, cis-aconitate and malate by 74%, 119% and 59%, respectively. OLETF showed 86% higher lactate and 38% lower ATP than those in LETO, but levels of the metabolites were normalized by empagliflozin, suggesting improved glucose oxidation. Conclusions The present analyses showed that amino acid and ketone metabolism are metabolic pathways that are most affected by empagliflozin. Coordination of these "starvation-induced pathways" may underlie the favorable metabolic effect of empagliflozin in T2DM hearts.

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