Understanding the molecular basis of the high oxygen affinity variant human hemoglobin Coimbra

Jorge, Susan E.; Bringas, Mauro; Petruk, Ariel Alcides; Arrar, Mehrnoosh; Martí, Marcelo A.; Skaf, Munir S.; Costa, Fernando Ferreira; Capece, Luciana; Sonati, María de Fátima; Estrin, Darı́o A.

doi:10.1016/j.abb.2017.11.010

Cited by 6 publications

(5 citation statements)

References 25 publications

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“…Several βAsp99 Hb variants, such as Hb Ypsilanti (βAsp99Tyr), Hb Radcliffe (βAsp99Ala), Hb Coimbra (βAsp99Glu) are known to exhibit increased affinity for O 2 and decreased cooperativity (Jorge et al 2018). These individuals are clinically characterized by erythrocytosis (Hardison et al 1994(Hardison et al , 2001Riemer et al 1998).…”

Section: Hemoglobin Variants With Altered Oxygen Affinitymentioning

confidence: 99%

“…The βAsp99 residue is located at the switch region of α1β2 dimer interface and forms unique hydrogen-bond interactions with α1Tyr42 and α1Asn97, stabilizing the T structure. Mutations of βAsp99 abrogate these hydrogen-bond interactions, shifting the allosteric equilibrium to the R state, and increasing Hb affinity for oxygen (Jorge et al 2018).…”

Section: Hemoglobin Variants With Altered Oxygen Affinitymentioning

confidence: 99%

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Hemoglobin: Structure, Function and Allostery

Ahmed

Ghatge

Safo

2020

Subcellular Biochemistry

158

141

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This chapter reviews how allosteric (heterotrophic) effectors and natural mutations impact hemoglobin (Hb) primary physiological function of oxygen binding and transport. First, an introduction about the structure of Hb is provided, including the ensemble of tense and relaxed Hb states and the dynamic equilibrium of Hb multistate. This is followed by a brief review of Hb variants with altered Hb structure and oxygen binding properties. Finally, a review of different endogenous and exogenous allosteric effectors of Hb is presented with particular emphasis on the atomic interactions of synthetic ligands with altered allosteric function of Hb that could potentially be harnessed for the treatment of diseases.

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Section: Hemoglobin Variants With Altered Oxygen Affinitymentioning

confidence: 99%

Section: Hemoglobin Variants With Altered Oxygen Affinitymentioning

confidence: 99%

Hemoglobin: Structure, Function and Allostery

Ahmed

Ghatge

Safo

2020

Subcellular Biochemistry

158

141

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“…First, we considered the protonation of the four distal histidines (E7) forming only the neutral tautomer with a proton in N ε (HIE), according to the Mb analysis, and equilibration was achieved, as in the Mb and NP 4 examples. Then, we run MD simulations, assessing the absence of allosteric modifications during the experiment by checking that the initial and final angle between dimers α 1 β 1 and α 2 β 2 remained unchanged . For the optimized structure, we performed three 100 ns MD simulations (3 × 100 ns).…”

Section: Theoretical Calculationsmentioning

confidence: 99%

“…Then, we run MD simulations, assessing the absence of allosteric modifications during the experiment by checking that the initial and final angle between dimers α 1 β 1 and α 2 β 2 remained unchanged. 80 For the optimized structure, we performed three 100 ns MD simulations (3 × 100 ns).…”

Section: ■ Introductionmentioning

confidence: 99%

In Silico Insight into the Reductive Nitrosylation of Ferric Hemeproteins

2020

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A combination of in silico methods was used to extend the experimental description of the reductive nitrosylation mechanism in ferric hemeproteins with the molecular details of the role of surrounding amino acids. The computational strategy consisted in the estimation of potential energy profiles for the transition process associated with the interactions of the coordinated N(NO) moiety with O(H 2 O) or O(OH − ) as nucleophiles, and with distal amino acids as proton acceptors or affecting the stability of transition states. We inspected the reductive nitrosylation in three representative hemeproteins -sperm whale metmyoglobin, α subunit of human methemoglobin and nitrophorin 4 of Rhodnius prolixus. For each case, classical molecular dynamics simulations were performed in order to obtain relevant reactive conformations, and a potential energy profile for the reactive step was obtained using adiabatic mapping or nudged elastic band approaches at the QM/MM level. Specifically, we report the role of a charged Arg45 of myoglobin in destabilizing the transition state when H 2 O acts as nucleophile, differently to the neutral Pro43 of the hemoglobin subunit. The case of the nitrophorin is unique in that the access of the required water molecules is scarce, thus, preventing the reaction.

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“…Previously, researchers admitted that the base of hemoglobin allosterism was based on the Monod Wyman-Changeux (MWC) two-state allosteric model, which corresponded to oxyhemoglobin (bound) and deoxyhemoglobin (unlinked) forms [44,46,49]. It is currently believed that hemoglobin can adopt several allosteric conformations in dynamic equilibrium, also implying different functionalities ( Figure 4) [44,48].…”

Section: The Hemoglobin: Origins and Functionmentioning

confidence: 99%

Sickle Cell Disease: A Genetic Disorder of Beta-Globin

Cordovil¹

2018

Thalassemia and Other Hemolytic Anemias

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Sickle cell disease (SCD) is a structural and monogenetic genetic disorder due to a mutation that occurs in the globin β-chain, resulting in the formation of hemoglobin S (Hb S), a protein composed of two normal, and two β-type mutant chains. Estimates indicate that the prevalence among live births is 4.4% in the world. The difficulty in circulating the sickle cell, its interaction with endothelial cells, leukocytes, platelets, endothelial dysfunction, and the abnormal expression of adhesion molecules permeate the beginning of the blood vessel occlusion process as well as pathophysiological aspects of SCD. Among the secondary complications are the stroke, pulmonary hypertension, leg ulcer, renal disorders, and all complications associated with vascular dysfunction. Clinical and biochemical markers of disease severity can be used to predict risk, prevent complications, and increase the expectation and quality of life of the SCD population. The entire scenario generated by Hb S has implications for the health and social inclusion of patients, so the treatment of the person with SCD needs an approach focused on the prevention of these complications in an individualized way.

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Understanding the molecular basis of the high oxygen affinity variant human hemoglobin Coimbra

Cited by 6 publications

References 25 publications

Hemoglobin: Structure, Function and Allostery

Hemoglobin: Structure, Function and Allostery

In Silico Insight into the Reductive Nitrosylation of Ferric Hemeproteins

Sickle Cell Disease: A Genetic Disorder of Beta-Globin

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