Hemoglobin Kirklareli (α H58L), a New Variant Associated with Iron Deficiency and Increased CO Binding

Bissé, Emmanuel; Schaeffer-Reiss, Christine; Dorsselaer, Alain Van; Alayi, Tchilabalo Dilezitoko; Epting, Thomas; Winkler, Karl; Cardenas, Andres S. Benitez; Soman, Jayashree; Birukou, Ivan; Samuel, Premila P.; Olson, John S.

doi:10.1074/jbc.m116.764274

Cited by 16 publications

(24 citation statements)

References 67 publications

(59 reference statements)

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“…The imidazole sidechain of αHis58 provides stability to the heme bound O 2 through hydrogen-bond interactions, which is lost with αLeu58. Indeed, the crystal structure of Hb Kirklareli shows that the bound O 2 is no longer stabilized, consistent with the observed increased autoxidation and loss of hemin ~200 times more rapidly than native α subunits (Bissé et al 2017). Interestingly, Hb Kirklareli α subunit has an ~80,000-fold higher affinity for CO than O 2 , causing it to rapidly take up and retain carbon monoxide (Bissé et al 2017).…”

Section: Hemoglobin Variants With Altered Oxygen Affinitysupporting

confidence: 52%

“…Mutations in the heme pocket are also known to affect Hb oxygen binding properties (Thom et al 2013). An example is Hb Kirklareli (αHis58Leu), which is associated with iron deficiency and increased CO binding (Bissé et al 2017). The imidazole sidechain of αHis58 provides stability to the heme bound O 2 through hydrogen-bond interactions, which is lost with αLeu58.…”

Section: Hemoglobin Variants With Altered Oxygen Affinitymentioning

confidence: 99%

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Hemoglobin: Structure, Function and Allostery

Ahmed

Ghatge

Safo

2020

Subcellular Biochemistry

172

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 Affinitysupporting

confidence: 52%

Section: Hemoglobin Variants With Altered Oxygen Affinitymentioning

confidence: 99%

Hemoglobin: Structure, Function and Allostery

Ahmed

Ghatge

Safo

2020

Subcellular Biochemistry

172

141

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“…This effect was supported in vivo by data showing that upon CO treatment or after HO-1 induction, the levels of extracellular free heme in the circulation, significantly increased by the infection, nearly returned to basal values. Most striking are very recent data published by Bisse and colleagues (12) supporting this concept in humans. The authors identified a new mutated form of Hb (Hb Kirklareli) in a female patient and her father.…”

Section: Co As a Protector Of Heme Oxidationmentioning

confidence: 83%

“…A biochemical analysis of Hb Kirklareli shows that the mutant ␣-subunit of the protein autooxidizes~8 times more and loses heme~200 times faster than the native subunit. Interestingly, the affinity of Hb Kirklareli for CO is~80,000-fold higher than for O 2 , explaining why the father, being a smoker, is protected against heme oxidation and Hb denaturation (12).…”

Section: Co As a Protector Of Heme Oxidationmentioning

confidence: 99%

Biological signaling by carbon monoxide and carbon monoxide-releasing molecules

Motterlini

Foresti

2017

American Journal of Physiology-Cell Physiology

202

145

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Carbon monoxide (CO) is continuously produced in mammalian cells during the degradation of heme. It is a stable gaseous molecule that reacts selectively with transition metals in a specific redox state, and these characteristics restrict the interaction of CO with defined biological targets that transduce its signaling activity. Because of the high affinity of CO for ferrous heme, these targets can be grouped into heme-containing proteins, representing a large variety of sensors and enzymes with a series of diverse function in the cell and the organism. Despite this notion, progress in identifying which of these targets are selective for CO has been slow and even the significance of elevated carbonmonoxy hemoglobin, a classical marker used to diagnose CO poisoning, is not well understood. This is also due to the lack of technologies capable of assessing in a comprehensive fashion the distribution and local levels of CO between the blood circulation, the tissue, and the mitochondria, one of the cellular compartments where CO exerts its signaling or detrimental effects. Nevertheless, the use of CO gas and CO-releasing molecules as pharmacological approaches in models of disease has provided new important information about the signaling properties of CO. In this review we will analyze the most salient effects of CO in biology and discuss how the binding of CO with key ferrous hemoproteins serves as a posttranslational modification that regulates important processes as diverse as aerobic metabolism, oxidative stress, and mitochondrial bioenergetics.

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“…Over the years, control and management of Hb disorders have encountered major economic and organizational difficulties [18]. Mutations in hemoglobin can cause a wide range of phenotypic outcomes, including anemia due to protein instability and red cell lysis [19] and occlusion of the microvascular circulation leading to tissue ischaemia, infarction, and chronic hemolytic anemia [20]. Knowledge in hemoglobin variants and carrier status is thus necessary in reproductive decision making to modify risk for offspring of serious conditions such as sickle cell anemia as well as provide direct health benefit to carriers [21].…”

Section: Discussionmentioning

confidence: 99%

Assessment of Hemoglobin Variants in Patients Receiving Health Care at the Ho Teaching Hospital: A Three-Year Retrospective Study

Awaitey

Akorsu

Allotey

et al. 2020

Advances in Hematology

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Background. It is estimated that one out of every three Ghanaians has hemoglobin genotype mutation. This change in genetic make-up may result in genotypes such as HbAS, HbSS, and HbSC. Many children in low- and middle-income countries die even before they are diagnosed with sickle cell disease (SCD). In Africa, there are limited data on the incidence and prevalence of SCD and the Volta region of Ghana is no exception. Aim. The aim of this study was to determine the prevalence of SCD and to assess the hemoglobin variants among patients attending Ho Teaching Hospital. Methods. A retrospective study design was used to extract information from the Hospital Administration and Management Systems (HAMS) on the hemoglobin electrophoresis results and corresponding full blood count results of the SCD and sickle cell anemia (SCA) patients as well as patients who were asked to do Hb electrophoresis irrespective of their sickling status. Data were collected for the period January 2016 to December 2018. Sickle cell disease status was determined using the Hb genotypes from the Hb electrophoresis results. The full blood count was used to categorize the severity of anemia based on the hemoglobin concentration in the SCA and SCD patients. Results. A total of 1,523 subjects were included in the study of which the prevalence for sickle cell disease was 16.7%. The SCD genotypes included HbS (6.2%), HbSC (7.9%), and HbSF (2.6%). Hemoglobin C disease (HbCC) constituted 0.3% out of the total prevalence of SCD. The prevalence of anemia was 99.2%, with the severest form in HbS. Also, majority of the SCD patients had severe anemia. Difference in the severity of anemia was found to be significant among both male (P=0.006) and female (P=0.004) participants with SCD. Conclusion. Patients receiving health care at the Ho Teaching Hospital had different hemoglobin variants with HbAS recording the highest prevalence. The high incidence of hemoglobin AS implies the possibility of having an increased population of individuals with sickle cell disease in future if measures are not put in place to improve screening, counseling, and education of the public about the health threat SCD poses.

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Hemoglobin Kirklareli (α H58L), a New Variant Associated with Iron Deficiency and Increased CO Binding

Cited by 16 publications

References 67 publications

Hemoglobin: Structure, Function and Allostery

Hemoglobin: Structure, Function and Allostery

Biological signaling by carbon monoxide and carbon monoxide-releasing molecules

Assessment of Hemoglobin Variants in Patients Receiving Health Care at the Ho Teaching Hospital: A Three-Year Retrospective Study

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