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Carriage of Oxygen in Blood
Published in Peter Kam, Ian Power, Michael J. Cousins, Philip J. Siddal, Principles of Physiology for the Anaesthetist, 2020
Peter Kam, Ian Power, Michael J. Cousins, Philip J. Siddal
In the erythrocyte, haemoglobin is folded into a complex, convoluted shape with the haem enclosed in a cleft formed by the protein, forming loose bonds with amino acids within the globin chain. Haemoglobin can exist in two structural forms, the tense (T) form and the relaxed (R) form. The difference between the two forms is brought about by a slight rotation of one pair of subunits with respect to the other. Oxygen binds about 70 times more easily to haem in the relaxed form than in the tense form. As more haems bind to oxygen, the transition to the relaxed state occurs more readily and the affinity for O2 increases. Hence, as haemoglobin binds O2, the binding of further O2 molecules becomes easier until four O2 molecules have been bound, at which point the haemoglobin is saturated (Adair equation). The final stage of oxygenation (i.e. binding of the fourth O2 molecule) is substantially faster than the previous three. This is known as positive cooperativity. The conformation of the haemoglobin molecule is altered by physical and chemical factors (including temperature, hydrogen ion concentration, carbon dioxide and 2,3-diphosphoglycerate concentration). Such physicochemical factors can therefore change the affinity of haemoglobin for oxygen.
Carbon Monoxide Poisoning, Methemoglobinemia, and Sulfhemoglobinemia
Published in Harold R. Schumacher, William A. Rock, Sanford A. Stass, Handbook of Hematologic Pathology, 2019
At the molecular level, cooperativity is accounted for by the fact that hemoglobin can exist stably in only two fundamentally different conformations, one for the oxygenated molecule (R state), another for the deoxygenated molecule (T state), without intermediate conformations. One molecule of hemoglobin will bind 2 molecules of oxygen in the low-affinity conformation (T state).
Red Cells with High Oxygen Affinity Hemoglobins
Published in Ronald L. Nagel, Genetically Abnormal Red Cells, 2019
Hb Grady, Dakar — This abnormal hemoglobin amounts to 8 to 18% of the hemolysate, is electrophoretically fast, and corresponds to an alpha chain elongation due to a triresidue insertion between normal residues 118 and 119. Hb Grady has slightly increased oxygen affinity, lowered cooperativity, normal Bohr effect, and some instability. From a genetic point of view it probably arose by a mispairing between allelic α genes because no fifth α gene has been found, as would be predicted if a misparing between nonallelic α genes would have taken place. No clinical consequences of this abnormal Hb have been found.
Hb Q-Thailand heterozygosity unlinked with the (–α4.2/) α+-thalassemia deletion allele identified by long-read SMRT sequencing: hematological and molecular analyses
Published in Hematology, 2023
Danqing Qin, Jicheng Wang, Cuize Yao, Xiuqin Bao, Jie Liang, Li Du
Hb Q-Thailand is a slow-moving abnormal hemoglobin that is characterized by a substitution of aspartic acid with histidine at the 74th position of the normal α1-globin chain. This hemoglobin shows normal oxygen affinity, a normal Bohr effect and normal cooperativity because the substituted amino acid is nonfunctional [8]. It was first observed in 1958 by Vella et al. in Singapore and first discovered in the Chinese population in 1983 by Zeng et al. [9,10]. Hb Q-Thailand has a high detection rate in southern China and Southeast Asian countries, where it occurs mostly in a heterozygous or compound heterozygous state with α0-thalassemia, causing Hb Q-H disease [3,4,8,11–13]. Although Hb Q-Thailand has been found in various populations, the present study is the first to report a negative result for DNA analysis of the (–α4.2/) deletion.
A molecular perspective on identifying TRPV1 thermosensitive regions and disentangling polymodal activation
Published in Temperature, 2023
Dustin D. Luu, Aerial M. Owens, Mubark D. Mebrat, Wade D. Van Horn
In the concatemer and other studies, a Hill model of cooperativity can be used to assess the allosteric implications between multiple ligand-binding sites [189]. A Hill coefficient (Kd) for additional oxygen-binding molecules [190]. Highly positive cooperative events, like found in hemoglobin, will generally have minimal intermediate bound states with an “all or nothing” binding process. In the context of hemoglobin, which is exceptionally cooperative, it is typically found in either an unbound or fully bound state [191]. Conversely, negative cooperativity functions to decrease the affinity of ligand binding as more ligands bind the substrate. The outcomes of negative cooperativity are more populated and longer-lasting intermediate bound states [191]. A noncooperative process effectively has independent binding sites [191]. Analysis of the rTRPV1–CAP concatemer study identifies a Hill coefficient near unity, indicating that CAP activation is noncooperative. This appears to agree with the conclusion that CAP binding to a single subunit can fully open rTRPV1 [180]. In contrast, rTRPV1 concatemer proton activation exhibits positive cooperativity (4,180]. The reported differences in cooperativity between CAP and protons shines a light on mechanistically distinct TRPV1 activation modes and provide a vignette into the complexity of deciphering the polymodal crosstalk between activation modes.
Insights into the operational model of agonism of receptor dimers
Published in Expert Opinion on Drug Discovery, 2022
There are two kinds of dimers (Figure 1). Homodimers (Figure 1, left) consist of two identical receptors R for which a given agonist A has the same affinity (1/KA) and exerts the same operational efficacy τ. Two molecules of an agonist bound to two orthosteric binding sites exert allosteric interaction. The factor of binding cooperativity α quantifies the change in agonist affinity upon binding of the second molecule of agonist to the dimer. In the case of positive cooperativity, the affinity of two concurrently bound agonists is greater than the affinity of a single bound agonist and the value of binding cooperativity factor α is higher than 1. In the case of negative cooperativity, the affinity of two concurrently bound agonist molecules is smaller than the affinity of a single bound molecule and the value of binding cooperativity factor α is lower than 1. The change in operational efficacy τ upon binding of the second molecule of agonist to the dimer is quantified by efficacy cooperativity factor β. In analogy to binding cooperativity, values of β higher than 1 denote positive cooperativity leading to an increase in operational efficacy τ and values lower than 1 denote negative cooperativity leading to a decrease in τ.