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Hong Liu, Morayo Adebiyi, Rong Rong Liu, Anren Song, Jeanne Manalo, Yuan Edward Wen, Alexander Q Wen, Tingting Weng, Junsuk Ko, Modupe Idowu, Rodney E Kellems, Holger K Eltzschig, Michael R Blackburn, Harinder S Juneja, Yang Xia
Although excessive plasma adenosine is detrimental in sickle cell disease (SCD), the molecular mechanism underlying elevated circulating adenosine remains unclear. Here we report that the activity of soluble CD73, an ectonucleotidase producing extracellular adenosine, was significantly elevated in a murine model of SCD and correlated with increased plasma adenosine. Mouse genetic studies demonstrated that CD73 activity contributes to excessive induction of plasma adenosine and thereby promotes sickling, hemolysis, multiorgan damage, and disease progression...
August 14, 2018: Blood Advances
S E Jorge, M Bringas, A A Petruk, M Arrar, M A Marti, M S Skaf, F F Costa, L Capece, M F Sonati, D Estrin
Human hemoglobin (Hb) Coimbra (βAsp99Glu) is one of the seven βAsp99 Hb variants described to date. All βAsp99 substitutions result in increased affinity for O2 and decreased heme-heme cooperativity and their carriers are clinically characterized by erythrocytocis, caused by tissue hypoxia. Since βAsp99 plays an important role in the allosteric α1β2 interface and the mutation in Hb Coimbra only represents the insertion of a CH2 group in this interface, the present study of Hb Coimbra is important for a better understanding of the global impact of small modifications in this allosteric interface...
January 1, 2018: Archives of Biochemistry and Biophysics
Kaiqi Sun, Angelo D'Alessandro, Mostafa H Ahmed, Yujin Zhang, Anren Song, Tzu-Ping Ko, Travis Nemkov, Julie A Reisz, Hongyu Wu, Morayo Adebiyi, Zhangzhe Peng, Jing Gong, Hong Liu, Aji Huang, Yuan Edward Wen, Alexander Q Wen, Vladimir Berka, Mikhail V Bogdanov, Osheiza Abdulmalik, Leng Han, Ah-Lim Tsai, Modupe Idowu, Harinder S Juneja, Rodney E Kellems, William Dowhan, Kirk C Hansen, Martin K Safo, Yang Xia
Elevated sphingosine 1-phosphate (S1P) is detrimental in Sickle Cell Disease (SCD), but the mechanistic basis remains obscure. Here, we report that increased erythrocyte S1P binds to deoxygenated sickle Hb (deoxyHbS), facilitates deoxyHbS anchoring to the membrane, induces release of membrane-bound glycolytic enzymes and in turn switches glucose flux towards glycolysis relative to the pentose phosphate pathway (PPP). Suppressed PPP causes compromised glutathione homeostasis and increased oxidative stress, while enhanced glycolysis induces production of 2,3-bisphosphoglycerate (2,3-BPG) and thus increases deoxyHbS polymerization, sickling, hemolysis and disease progression...
November 10, 2017: Scientific Reports
Rob C Oslund, Xiaoyang Su, Michael Haugbro, Jung-Min Kee, Mark Esposito, Yael David, Boyuan Wang, Eva Ge, David H Perlman, Yibin Kang, Tom W Muir, Joshua D Rabinowitz
Lower glycolysis involves a series of reversible reactions, which interconvert intermediates that also feed anabolic pathways. 3-phosphoglycerate (3-PG) is an abundant lower glycolytic intermediate that feeds serine biosynthesis via the enzyme phosphoglycerate dehydrogenase, which is genomically amplified in several cancers. Phosphoglycerate mutase 1 (PGAM1) catalyzes the isomerization of 3-PG into the downstream glycolytic intermediate 2-phosphoglycerate (2-PG). PGAM1 needs to be histidine phosphorylated to become catalytically active...
October 2017: Nature Chemical Biology
Kehinde Onwochei Okonjo
As a prelude to separating tertiary from quaternary structure contributions to the Bohr effect, we employed the Wyman equation to analyze Bohr data for human hemoglobin to which 2,3-bisphosphoglycerate, 2,3-BPG, is bound. Changes in the pKa s of the histidine Bohr groups result in a net reduction of their contributions to the Bohr effect at pH 7.4 compared to their contributions in stripped hemoglobin. The non-histidine 2,3-BPG binding groups - the β-chain terminal amino group and Lys82β - make negative and positive contributions, respectively, to the Bohr effect...
September 2017: Biophysical Chemistry
Wei-Ren Chen, Youqing Yu, Muhammad Zulfajri, Ping-Cheng Lin, Chia C Wang
Angelica sinensis (AS), one of the most versatile herbal medicines remains widely used due to its multi-faceted pharmacologic activities. Besides its traditional use as the blood-nourishing tonic, its anti-hypertensive, anti-cardiovascular, neuroprotective and anti-cancer effects have been reported. Albeit the significant therapeutic effects, how AS exerts such diverse efficacies from the molecular level remains elusive. Here we investigate the influences of AS and four representative phthalide derivatives from AS on the structure and function of hemoglobin (Hb)...
July 14, 2017: Scientific Reports
Johan W Lagerberg, Herbert Korsten, Pieter F Van Der Meer, Dirk De Korte
BACKGROUND: In Europe, red cell concentrates (RCC) are usually stored in SAGM (saline-adenine-glucose-mannitol). During storage, in vitro red cell quality declines, including lowered energy status and increased cell lysis. Recently, several additive solutions (ASs), designed to diminish the decline in in vitro quality during storage, have been developed. These new solutions have mainly been developed to better maintain red blood cell (RBC) 2,3-biphosphoglycerate (2,3 BPG) levels and energy status during storage...
September 2017: Blood Transfusion
Hong Liu, Yujin Zhang, Hongyu Wu, Angelo D'Alessandro, Gennady G Yegutkin, Anren Song, Kaiqi Sun, Jessica Li, Ning-Yuan Cheng, Aji Huang, Yuan Edward Wen, Ting Ting Weng, Fayong Luo, Travis Nemkov, Hong Sun, Rodney E Kellems, Harry Karmouty-Quintana, Kirk C Hansen, Bihong Zhao, Andrew W Subudhi, Sonja Jameson-Van Houten, Colleen G Julian, Andrew T Lovering, Holger K Eltzschig, Michael R Blackburn, Robert C Roach, Yang Xia
BACKGROUND: High altitude is a challenging condition caused by insufficient oxygen supply. Inability to adjust to hypoxia may lead to pulmonary edema, stroke, cardiovascular dysfunction, and even death. Thus, understanding the molecular basis of adaptation to high altitude may reveal novel therapeutics to counteract the detrimental consequences of hypoxia. METHODS: Using high-throughput, unbiased metabolomic profiling, we report that the metabolic pathway responsible for production of erythrocyte 2,3-bisphosphoglycerate (2,3-BPG), a negative allosteric regulator of hemoglobin-O2 binding affinity, was significantly induced in 21 healthy humans within 2 hours of arrival at 5260 m and further increased after 16 days at 5260 m...
August 2, 2016: Circulation
Kaiqi Sun, Yujin Zhang, Angelo D'Alessandro, Travis Nemkov, Anren Song, Hongyu Wu, Hong Liu, Morayo Adebiyi, Aji Huang, Yuan E Wen, Mikhail V Bogdanov, Alejandro Vila, John O'Brien, Rodney E Kellems, William Dowhan, Andrew W Subudhi, Sonja Jameson-Van Houten, Colleen G Julian, Andrew T Lovering, Martin Safo, Kirk C Hansen, Robert C Roach, Yang Xia
Sphingosine-1-phosphate (S1P) is a bioactive signalling lipid highly enriched in mature erythrocytes, with unknown functions pertaining to erythrocyte physiology. Here by employing nonbiased high-throughput metabolomic profiling, we show that erythrocyte S1P levels rapidly increase in 21 healthy lowland volunteers at 5,260 m altitude on day 1 and continue increasing to 16 days with concurrently elevated erythrocyte sphingonisne kinase 1 (Sphk1) activity and haemoglobin (Hb) oxygen (O2) release capacity. Mouse genetic studies show that elevated erythrocyte Sphk1-induced S1P protects against tissue hypoxia by inducing O2 release...
July 15, 2016: Nature Communications
Jae Won Chang, Gihoon Lee, John S Coukos, Raymond E Moellering
Metabolomic profiling studies aim to provide a comprehensive, quantitative, and dynamic portrait of the endogenous metabolites in a biological system. While contemporary technologies permit routine profiling of many metabolites, intrinsically labile metabolites are often improperly measured or omitted from studies due to unwanted chemical transformations that occur during sample preparation or mass spectrometric analysis. The primary glycolytic metabolite 1,3-bisphosphoglyceric acid (1,3-BPG) typifies this class of metabolites, and, despite its central position in metabolism, has largely eluded analysis in profiling studies...
July 5, 2016: Analytical Chemistry
E S Belousova, Z I Mikashinowich, O G Sarkysjan
Concentration of glycolysis metabolites, activity of enzymes of carbohydrate and energetic metabolism and antioxidant enzymes was investigated in hepatocytes and erythrocytes with the purpose of estimation of functional metabolic changes of cells rebuilding after prolonged Simvastatin intake (Zocor, 20 mg; on 1.5 mg once a day during 3 months). It was established that total metabolic reaction on prolonged Simvastatin intake at intact animals characterized by hypoxia formation, that manifested by increasing of 2...
October 2015: Patologicheskaia Fiziologiia i èksperimental'naia Terapiia
William G O'Brien, Vladimir Berka, Ah-Lim Tsai, Zhaoyang Zhao, Cheng Chi Lee
Erythrocytes are the key target in 5'-AMP induced hypometabolism. To understand how regulation of endogenous erythrocyte AMP levels modulates systemic metabolism, we generated mice deficient in both CD73 and AMPD3, the key catabolic enzymes for extracellular and intra-erythrocyte AMP, respectively. Under physiological conditions, these mice displayed enhanced capacity for physical activity accompanied by significantly higher food and oxygen consumption, compared to wild type mice. Erythrocytes from Ampd3(-/-) mice exhibited higher half-saturation pressure of oxygen (p50) and about 3-fold higher levels of ATP and ADP, while they maintained normal 2,3-bisphosphoglycerate (2,3-BPG), methemoglobin levels and intracellular pH...
August 7, 2015: Scientific Reports
Rola Sahyoun Tokan, Saadet Arsan, Omer Erdeve, Nuri Solaz, Aslıhan Avcı, Serenay Elgün Ulkar, Elif Gülyapar, Zeynep Ustünyurt, Zeynep Bıyıklı, Sabri Kemahlı
OBJECTIVE: This study aimed to compare the storage properties of red blood cell (RBC) concentrates of umbilical cordblood (UCB) and adult donor blood (ADB), and to evaluate the feasibility of UCB-RBC concentrate as an autologoussource for blood transfusion in very low birth weight (VLBW) preterm neonates. MATERIAL AND METHODS: In all, 30 newborn (10 preterm, 20 full term) UCB and 31 ADB units were collected.RBC concentrates were stored and compared with regard to pH, potassium (K(+)), 2,3-biphosphoglycerate (2-3-BPG),adenosine tri-phosphate (ATP), plasma Hb, and bacterial contamination on d 1, 21, and 35 of storage...
September 2012: Turkish Journal of Haematology: Official Journal of Turkish Society of Haematology
Taiko Nishino, Ayako Yachie-Kinoshita, Akiyoshi Hirayama, Tomoyoshi Soga, Makoto Suematsu, Masaru Tomita
Although intraerythrocytic ATP and 2,3-bisphophoglycerate (2,3-BPG) are known as direct indicators of the viability of preserved red blood cells and the efficiency of post-transfusion oxygen delivery, no current blood storage method in practical use has succeeded in maintaining both these metabolites at high levels for long periods. In this study, we constructed a mathematical kinetic model of comprehensive metabolism in red blood cells stored in a recently developed blood storage solution containing adenine and guanosine, which can maintain both ATP and 2,3-BPG...
2013: PloS One
Yujin Zhang, Yang Xia
Sickle cell disease (SCD) is a debilitating hemolytic genetic disorder with high morbidity and mortality affecting millions of individuals worldwide. Although SCD was discovered more than a century ago, no effective mechanism-based prevention and treatment are available due to poorly understood molecular basis of sickling, the fundamental pathogenic process of the disease. SCD patients constantly face hypoxia. One of the best-known signaling molecules to be induced under hypoxic conditions is adenosine. Recent studies demonstrate that hypoxia-mediated elevated adenosine signaling plays an important role in normal erythrocyte physiology...
August 2012: Microbes and Infection
A Patterson, N C Price, J Nairn
Erythrocyte-specific bisphosphoglycerate mutase is a trifunctional enzyme which modulates the levels of 2,3-bisphosphoglycerate (2,3-BPG) in red blood cells by virtue of its synthase and phosphatase activities. Low levels of erythrocyte 2,3-BPG increase the affinity of haemoglobin for oxygen, thus limiting the release of oxygen into tissues. 2,3-BPG levels in stored blood decline rapidly owing to the phosphatase activity of bisphosphoglycerate mutase, which is enhanced by a fall in pH. Here, the 1.94 Å resolution X-ray structure of bisphosphoglycerate mutase is presented, focusing on the dynamic nature of key ligand-binding residues and their interaction with the inhibitor citrate...
November 1, 2010: Acta Crystallographica. Section F, Structural Biology and Crystallization Communications
Taiko Nishino, Ayako Yachie-Kinoshita, Akiyoshi Hirayama, Tomoyoshi Soga, Makoto Suematsu, Masaru Tomita
There is currently no effective method for preventing ATP and 2,3-bisphosphoglycerate (2,3-BPG) depletion during long-term erythrocyte storage in the cold, although these metabolites are strongly associated with cell viability and oxygen delivery after transfusion. Metabolite reduction is caused by whole metabolic networks in the cell, which are regulated by various physical or chemical factors. Mathematical modeling is a powerful tool for integrating such complex and dynamic systems. Here, we developed a mathematical model to predict metabolism in erythrocytes preserved with a mannitol-adenine-phosphate solution (MAP) at 4 degrees C, by modifying a published model of large-scale erythrocyte metabolism...
November 2009: Journal of Biotechnology
Barbara Manconi, Irene Messana, Federica Maggiani, Alessandra Olianas, Mariagiuseppina Pellegrini, Roberto Crnjar, Massimo Castagnola, Bruno Giardina, Maria Teresa Sanna
Structural analysis of the hemoglobin (Hb) system of Delphinus delphis revealed a high globin multiplicity: HPLC-electrospray ionization-mass spectrometry (ESI-MS) analysis evidenced three major beta (beta1 16,022 Da, beta2 16,036 Da, beta3 16,036 Da, labeled according to their progressive elution times) and two major alpha globins (alpha1 15,345 Da, alpha2 15,329 Da). ESI-tandem mass and nucleotide sequence analyses showed that beta2 globin differs from beta1 for the substitution Val126 --> Leu, while beta3 globin differs from beta2 for the isobaric substitution Lys65 --> Gln...
November 2009: Journal of Comparative Physiology. B, Biochemical, Systemic, and Environmental Physiology
Bjørn Hald, Mads F Madsen, Sune Danø, Bjørn Quistorff, Preben G Sørensen
The changes in the partial pressures of oxygen and carbon dioxide (P(O(2)) and P(CO(2))) during blood circulation alter erythrocyte metabolism, hereby causing flux changes between oxygenated and deoxygenated blood. In the study we have modeled this effect by extending the comprehensive kinetic model by Mulquiney and Kuchel [P.J. Mulquiney, and P.W. Kuchel. Model of 2,3-bisphosphoglycerate metabolism in the human erythrocyte based on detailed enzyme kinetic equations: equations and parameter refinement, Biochem...
April 2009: Biophysical Chemistry
Jaiesoon Cho, Jason S King, Xun Qian, Adrian J Harwood, Stephen B Shears
The Rapoport-Luebering glycolytic bypass comprises evolutionarily conserved reactions that generate and dephosphorylate 2,3-bisphosphoglycerate (2,3-BPG). For >30 years, these reactions have been considered the responsibility of a single enzyme, the 2,3-BPG synthase/2-phosphatase (BPGM). Here, we show that Dictyostelium, birds, and mammals contain an additional 2,3-BPG phosphatase that, unlike BPGM, removes the 3-phosphate. This discovery reveals that the glycolytic pathway can bypass the formation of 3-phosphoglycerate, which is a precursor for serine biosynthesis and an activator of AMP-activated protein kinase...
April 22, 2008: Proceedings of the National Academy of Sciences of the United States of America
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