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Heme and Hemopexin: Multitasking Molecules
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Heme and Hemopexin: Multitasking Molecules

A special issue of International Journal of Molecular Sciences (ISSN 1422-0067). This special issue belongs to the section "Molecular Pathology, Diagnostics, and Therapeutics".

Deadline for manuscript submissions: closed (28 February 2022) | Viewed by 13820

Special Issue Editor

Dr. William T. Morgan

E-Mail Website
Guest Editor
University of Missouri-Kansas City, Kansas City, MO, USA

Special Issue Information

Dear Colleagues,

Hemopexin (HPX) is a plasma glycoprotein with the strongest known binding affinity for heme. The complete 3D structure of HPX is known and consists of two 4-bladed β-propeller domains connected by a linker region. The HPX domain motif is found in matrix metalloproteinases (MMPs), vitronectin, and proteoglycan 4 gene products, and could possibly enable HPX to form a variety of molecular complexes with varied cellular consequences. In addition to clearing potentially toxic heme from the circulation and enabling the reclamation of metabolically vital iron, HPX is increasingly being found to act in the modulation of diverse physiological and pathophysiological cellular processes. For example, evidence indicates that HPX is an anti-oxidant and has potential roles in inhibiting apoptosis and in immune regulation. Further, HPX is also implicated in affecting cell differentiation and possibly extracellular matrix reconstruction. To fulfill its functions, HPX must interact with and enter cells. Hepatocytes, lymphocytes, and H. influenzae b among others are reported to possess HPX receptors. However, the characterization of HPX receptor(s) remains incomplete. Although progress has been made in our understanding of the mechanisms of HPX actions and related biological effects, there is a pressing need for more information. Importantly, although HPX levels correlate with hemolytic states, further clinical ramifications of hemopexin as a biomarker in various diseases including cancers of lung, liver, kidney, colon, and uterus, osteoarthritis, and pre-eclampsia require careful evaluation. This Special Issue is intended to extend and refine knowledge of this fascinating protein.

Dr. William T. Morgan
Guest Editor

Manuscript Submission Information

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Submitted manuscripts should not have been published previously, nor be under consideration for publication elsewhere (except conference proceedings papers). All manuscripts are thoroughly refereed through a single-blind peer-review process. A guide for authors and other relevant information for submission of manuscripts is available on the Instructions for Authors page. International Journal of Molecular Sciences is an international peer-reviewed open access semimonthly journal published by MDPI.

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Keywords

  • Hemopexin
  • Heme transport
  • Heme toxicity
  • Anti-oxidant
  • Iron conservation
  • Matrix metalloproteinase
  • Hemopexin receptor

Published Papers (4 papers)

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Research

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11 pages, 2089 KiB  
Article
New Insights into Hemopexin-Binding to Hemin and Hemoglobin
by Guilherme C. Lechuga, Paloma Napoleão-Pêgo, Carlos M. Morel, David W. Provance and Salvatore G. De-Simone
Int. J. Mol. Sci. 2022, 23(7), 3789; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms23073789 - 30 Mar 2022
Cited by 4 | Viewed by 1873
Abstract
Hemopexin (Hx) is a plasma glycoprotein that scavenges heme (Fe(III) protoporphyrin IX). Hx has important implications in hemolytic disorders and hemorrhagic conditions because releasing hemoglobin increases the labile heme, which is potentially toxic, thus producing oxidative stress. Therefore, Hx has been considered for [...] Read more.
Hemopexin (Hx) is a plasma glycoprotein that scavenges heme (Fe(III) protoporphyrin IX). Hx has important implications in hemolytic disorders and hemorrhagic conditions because releasing hemoglobin increases the labile heme, which is potentially toxic, thus producing oxidative stress. Therefore, Hx has been considered for therapeutic use and diagnostics. In this work, we analyzed and mapped the interaction sequences of Hx with hemin and hemoglobin. The spot-synthesis technique was used to map human hemopexin (P02790) binding to hemin and human hemoglobin. A library of 15 amino acid peptides with a 10-amino acid overlap was designed to represent the entire coding region (aa 1-462) of hemopexin and synthesized onto cellulose membranes. An in silico approach was taken to analyze the amino acid frequency in the identified interaction regions, and molecular docking was applied to assess the protein-protein interaction. Seven linear peptide sequences in Hx were identified to bind hemin (H1–H7), and five were described for Hb (Hb1–Hb5) interaction, with just two sequences shared between hemin and Hb. The amino acid composition of the identified sequences demonstrated that histidine residues are relevant for heme binding. H105, H293, H373, H400, H429, and H462 were distributed in the H1–H7 peptide sequences, but other residues may also play an important role. Molecular docking analysis demonstrated Hx’s association with the β-chain of Hb, with several hotspot amino acids that coordinated the interaction. This study provides new insights into Hx-hemin binding motifs and protein-protein interactions with Hb. The identified binding sequences and specific peptides can be used for therapeutic purposes and diagnostics as hemopexin is under investigation to treat different diseases and there is an urgent need for diagnostics using labile heme when monitoring hemolysis. Full article
(This article belongs to the Special Issue Heme and Hemopexin: Multitasking Molecules)
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18 pages, 13922 KiB  
Article
Human Plasma and Recombinant Hemopexins: Heme Binding Revisited
by Elena Karnaukhova, Catherine Owczarek, Peter Schmidt, Dominik J. Schaer and Paul W. Buehler
Int. J. Mol. Sci. 2021, 22(3), 1199; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms22031199 - 26 Jan 2021
Cited by 8 | Viewed by 3073
Abstract
Plasma hemopexin (HPX) is the key antioxidant protein of the endogenous clearance pathway that limits the deleterious effects of heme released from hemoglobin and myoglobin (the term “heme” is used in this article to denote both the ferrous and ferric forms). During intra-vascular [...] Read more.
Plasma hemopexin (HPX) is the key antioxidant protein of the endogenous clearance pathway that limits the deleterious effects of heme released from hemoglobin and myoglobin (the term “heme” is used in this article to denote both the ferrous and ferric forms). During intra-vascular hemolysis, heme partitioning to protein and lipid increases as the plasma concentration of HPX declines. Therefore, the development of HPX as a replacement therapy during high heme stress could be a relevant intervention for hemolytic disorders. A logical approach to enhance HPX yield involves recombinant production strategies from human cell lines. The present study focuses on a biophysical assessment of heme binding to recombinant human HPX (rhHPX) produced in the Expi293FTM (HEK293) cell system. In this report, we examine rhHPX in comparison with plasma HPX using a systematic analysis of protein structural and functional characteristics related to heme binding. Analysis of rhHPX by UV/Vis absorption spectroscopy, circular dichroism (CD), size-exclusion chromatography (SEC)-HPLC, and catalase-like activity demonstrated a similarity to HPX fractionated from plasma. In particular, the titration of HPX apo-protein(s) with heme was performed for the first time using a wide range of heme concentrations to model HPX–heme interactions to approximate physiological conditions (from extremely low to more than two-fold heme molar excess over the protein). The CD titration data showed an induced bisignate CD Soret band pattern typical for plasma and rhHPX versions at low heme-to-protein molar ratios and demonstrated that further titration is dependent on the amount of protein-bound heme to the extent that the arising opposite CD couplet results in a complete inversion of the observed CD pattern. The data generated in this study suggest more than one binding site in both plasma and rhHPX. Furthermore, our study provides a useful analytical platform for the detailed characterization of HPX–heme interactions and potentially novel HPX fusion constructs. Full article
(This article belongs to the Special Issue Heme and Hemopexin: Multitasking Molecules)
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Review

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15 pages, 911 KiB  
Review
Critical Role of Hemopexin Mediated Cytoprotection in the Pathophysiology of Sickle Cell Disease
by Rani Ashouri, Madison Fangman, Alicia Burris, Miriam O. Ezenwa, Diana J. Wilkie and Sylvain Doré
Int. J. Mol. Sci. 2021, 22(12), 6408; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms22126408 - 15 Jun 2021
Cited by 11 | Viewed by 5307
Abstract
Circulating hemopexin is the primary protein responsible for the clearance of heme; therefore, it is a systemic combatant against deleterious inflammation and oxidative stress induced by the presence of free heme. This role of hemopexin is critical in hemolytic pathophysiology. In this review, [...] Read more.
Circulating hemopexin is the primary protein responsible for the clearance of heme; therefore, it is a systemic combatant against deleterious inflammation and oxidative stress induced by the presence of free heme. This role of hemopexin is critical in hemolytic pathophysiology. In this review, we outline the current research regarding how the dynamic activity of hemopexin is implicated in sickle cell disease, which is characterized by a pathological aggregation of red blood cells and excessive hemolysis. This pathophysiology leads to symptoms such as acute kidney injury, vaso-occlusion, ischemic stroke, pain crises, and pulmonary hypertension exacerbated by the presence of free heme and hemoglobin. This review includes in vivo studies in mouse, rat, and guinea pig models of sickle cell disease, as well as studies in human samples. In summary, the current research indicates that hemopexin is likely protective against these symptoms and that rectifying depleted hemopexin in patients with sickle cell disease could improve or prevent the symptoms. The data compiled in this review suggest that further preclinical and clinical research should be conducted to uncover pathways of hemopexin in pathological states to evaluate its potential clinical function as both a biomarker and therapy for sickle cell disease and related hemoglobinopathies. Full article
(This article belongs to the Special Issue Heme and Hemopexin: Multitasking Molecules)
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Other

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6 pages, 405 KiB  
Commentary
Hemopexin and Cancer
by Veronica Fiorito and Emanuela Tolosano
Int. J. Mol. Sci. 2022, 23(2), 997; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms23020997 - 17 Jan 2022
Cited by 5 | Viewed by 2688
Abstract
Hemopexin is the plasma protein with the highest affinity for heme. Seminal studies have highlighted its role in different kinds of heme-associated disorders, but its implication in cancer has been neglected for a long time. Considering the emerging importance of heme in tumors, [...] Read more.
Hemopexin is the plasma protein with the highest affinity for heme. Seminal studies have highlighted its role in different kinds of heme-associated disorders, but its implication in cancer has been neglected for a long time. Considering the emerging importance of heme in tumors, the present review proposes an update of the works investigating hemopexin involvement in cancer, with the attempt to stimulate further future studies on this topic. Full article
(This article belongs to the Special Issue Heme and Hemopexin: Multitasking Molecules)
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