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Biomolecules
Special Issues
Unraveling Mysteries of Heme Metabolism
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Unraveling Mysteries of Heme Metabolism

A special issue of Biomolecules (ISSN 2218-273X). This special issue belongs to the section "Molecular Biology".

Deadline for manuscript submissions: closed (30 April 2024) | Viewed by 11481

Special Issue Editors

Prof. Dr. Harry A. Dailey

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Guest Editor
1. Department of Biochemistry and Molecular Biology, University of Georgia, Athens, GA 30602, USA
2. Department of Microbiology, University of Georgia, Athens, GA 30602, USA
Interests: heme biosynthesis; erythropoiesis; membrane proteins
Prof. Dr. Peter N. Meissner

E-Mail Website1 Website2
Guest Editor
1. Department of Integrative Biomedical Sciences (Medical Biochemistry), University of Cape Town Medical School, Observatory 7925, Cape Town, South Africa
2. Research Office, Otto Beit Building, University of Cape Town, Rondebosch, 7700, Cape Town, South Africa
Interests: heme biosynthesis; porphyria; porphyrins; enzymes; postgraduate education
Dr. Amy E. Medlock

E-Mail Website
Guest Editor
1. Department of Biochemistry and Molecular Biology, University of Georgia, Athens, GA 30602, USA
2. Augusta University/University of Georgia Medical Partnership, University of Georgia, Athens, GA 30602, USA
Interests: heme biosynthesis; protein–protein interactions; erythropoiesis; regulation of heme synthesis
Prof. Dr. John D. Phillips

E-Mail Website1 Website2
Guest Editor
Division of Hematology, University of Utah School of Medicine, Salt Lake City, UT 84132, USA
Interests: porphyria; heme biosynthesis; biochemistry; honeybees
Prof. Dr. Iqbal Hamza

E-Mail Website
Guest Editor
1. Center for Blood Oxygen Transport and Hemostasis, Department of Pediatrics, University of Maryland, Baltimore, MD 21201, USA
2. Department of Animal & Avian Sciences, University of Maryland, College Park, MD 20742, USA
Interests: heme trafficking; red cells; anemia; parasites

Special Issue Information

Dear Colleagues,

Heme, an iron-containing cofactor, is essential for most life forms. Heme-containing proteins are responsible for a myriad of different tasks in living organisms, being responsible for electron transfer, gas transport and sensing, diverse one-electron enzymatic reactions, and as gene regulators to list a few. The ability of the iron to change valance rapidly upon coordination with a ligand provides a diverse functionality to the array of biomolecules. While most currently characterized organisms that possess heme are capable of synthesizing their own heme, some do not, and have evolved elaborate mechanisms to obtain heme from their environment. Among mammals, defects in the heme synthesis pathway result in phenotypic disorders named porphyrias. Additionally, heme may be further metabolized to yield linear tetrapyrroles which serve diverse functions. The collection of papers assembled herein emanates from the 2023 Cape Town conference entitled "Unraveling Mysteries of Heme Metabolism”. At this conference, novel unpublished data were presented that shed light on our current understanding of this fascinating and challenging field, in addition to providing a road map for significant areas of future research.

Prof. Dr. Harry A. Dailey
Prof. Dr. Peter N. Meissner
Dr. Amy E. Medlock
Prof. Dr. John D. Phillips 
Prof. Dr. Iqbal Hamza
Guest Editors

Manuscript Submission Information

Manuscripts should be submitted online at www.mdpi.com by registering and logging in to this website. Once you are registered, click here to go to the submission form. Manuscripts can be submitted until the deadline. All submissions that pass pre-check are peer-reviewed. Accepted papers will be published continuously in the journal (as soon as accepted) and will be listed together on the special issue website. Research articles, review articles as well as short communications are invited. For planned papers, a title and short abstract (about 100 words) can be sent to the Editorial Office for announcement on this website.

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. Biomolecules is an international peer-reviewed open access monthly journal published by MDPI.

Please visit the Instructions for Authors page before submitting a manuscript. The Article Processing Charge (APC) for publication in this open access journal is 2700 CHF (Swiss Francs). Submitted papers should be well formatted and use good English. Authors may use MDPI's English editing service prior to publication or during author revisions.

Keywords

  • heme synthesis
  • heme metabolism
  • metabolic disorders
  • tetrapyrroles
  • heme proteins

Published Papers (7 papers)

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Research

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19 pages, 4840 KiB  
Article
FLVCR1a Controls Cellular Cholesterol Levels through the Regulation of Heme Biosynthesis and Tricarboxylic Acid Cycle Flux in Endothelial Cells
by Marta Manco, Giorgia Ammirata, Sara Petrillo, Francesco De Giorgio, Simona Fontana, Chiara Riganti, Paolo Provero, Sharmila Fagoonee, Fiorella Altruda and Emanuela Tolosano
Biomolecules 2024, 14(2), 149; https://doi.org/10.3390/biom14020149 - 26 Jan 2024
Cited by 1 | Viewed by 1043
Abstract
Feline leukemia virus C receptor 1a (FLVCR1a), initially identified as a retroviral receptor and localized on the plasma membrane, has emerged as a crucial regulator of heme homeostasis. Functioning as a positive regulator of δ-aminolevulinic acid synthase 1 (ALAS1), the rate-limiting enzyme in [...] Read more.
Feline leukemia virus C receptor 1a (FLVCR1a), initially identified as a retroviral receptor and localized on the plasma membrane, has emerged as a crucial regulator of heme homeostasis. Functioning as a positive regulator of δ-aminolevulinic acid synthase 1 (ALAS1), the rate-limiting enzyme in the heme biosynthetic pathway, FLVCR1a influences TCA cycle cataplerosis, thus impacting TCA flux and interconnected metabolic pathways. This study reveals an unexplored link between FLVCR1a, heme synthesis, and cholesterol production in endothelial cells. Using cellular models with manipulated FLVCR1a expression and inducible endothelial-specific Flvcr1a-null mice, we demonstrate that FLVCR1a-mediated control of heme synthesis regulates citrate availability for cholesterol synthesis, thereby influencing cellular cholesterol levels. Moreover, alterations in FLVCR1a expression affect membrane cholesterol content and fluidity, supporting a role for FLVCR1a in the intricate regulation of processes crucial for vascular development and endothelial function. Our results underscore FLVCR1a as a positive regulator of heme synthesis, emphasizing its integration with metabolic pathways involved in cellular energy metabolism. Furthermore, this study suggests that the dysregulation of heme metabolism may have implications for modulating lipid metabolism. We discuss these findings in the context of FLVCR1a’s potential heme-independent function as a choline importer, introducing additional complexity to the interplay between heme and lipid metabolism. Full article
(This article belongs to the Special Issue Unraveling Mysteries of Heme Metabolism)
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22 pages, 5271 KiB  
Article
Exploiting Differences in Heme Biosynthesis between Bacterial Species to Screen for Novel Antimicrobials
by Laurie K. Jackson, Tammy A. Dailey, Brenden Anderle, Martin J. Warren, Hector A. Bergonia, Harry A. Dailey and John D. Phillips
Biomolecules 2023, 13(10), 1485; https://doi.org/10.3390/biom13101485 - 06 Oct 2023
Cited by 1 | Viewed by 2327
Abstract
The final three steps of heme biogenesis exhibit notable differences between di- and mono-derm bacteria. The former employs the protoporphyrin-dependent (PPD) pathway, while the latter utilizes the more recently uncovered coproporphyrin-dependent (CPD) pathway. In order to devise a rapid screen for potential inhibitors [...] Read more.
The final three steps of heme biogenesis exhibit notable differences between di- and mono-derm bacteria. The former employs the protoporphyrin-dependent (PPD) pathway, while the latter utilizes the more recently uncovered coproporphyrin-dependent (CPD) pathway. In order to devise a rapid screen for potential inhibitors that differentiate the two pathways, the genes associated with the protoporphyrin pathway in an Escherichia coli YFP strain were replaced with those for the CPD pathway from Staphylococcus aureus (SA) through a sliding modular gene replacement recombineering strategy to generate the E. coli strain Sa-CPD-YFP. Potential inhibitors that differentially target the pathways were identified by screening compound libraries against the YFP-producing Sa-CPD-YFP strain in comparison to a CFP-producing E. coli strain. Using a mixed strain assay, inhibitors targeting either the CPD or PPD heme pathways were identified through a decrease in one fluorescent signal but not the other. An initial screen identified both azole and prodigiosin-derived compounds that were shown to specifically target the CPD pathway and which led to the accumulation of coproheme, indicating that the main target of inhibition would appear to be the coproheme decarboxylase (ChdC) enzyme. In silico modeling highlighted that these inhibitors are able to bind within the active site of ChdC. Full article
(This article belongs to the Special Issue Unraveling Mysteries of Heme Metabolism)
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15 pages, 3039 KiB  
Article
The Radical SAM Heme Synthase AhbD from Methanosarcina barkeri Contains Two Auxiliary [4Fe-4S] Clusters
by Isabelle Fix, Lorenz Heidinger, Thorsten Friedrich and Gunhild Layer
Biomolecules 2023, 13(8), 1268; https://doi.org/10.3390/biom13081268 - 18 Aug 2023
Viewed by 929
Abstract
In archaea and sulfate-reducing bacteria, heme is synthesized via the siroheme-dependent pathway. The last step of this route is catalyzed by the Radical SAM enzyme AhbD and consists of the conversion of iron-coproporphyrin III into heme. AhbD belongs to the subfamily of Radical [...] Read more.
In archaea and sulfate-reducing bacteria, heme is synthesized via the siroheme-dependent pathway. The last step of this route is catalyzed by the Radical SAM enzyme AhbD and consists of the conversion of iron-coproporphyrin III into heme. AhbD belongs to the subfamily of Radical SAM enzymes containing a SPASM/Twitch domain carrying either one or two auxiliary iron–sulfur clusters in addition to the characteristic Radical SAM cluster. In previous studies, AhbD was reported to contain one auxiliary [4Fe-4S] cluster. In this study, the amino acid sequence motifs containing conserved cysteine residues in AhbD proteins from different archaea and sulfate-reducing bacteria were reanalyzed. Amino acid sequence alignments and computational structural models of AhbD suggested that a subset of AhbD proteins possesses the full SPASM motif and might contain two auxiliary iron–sulfur clusters (AuxI and AuxII). Therefore, the cluster content of AhbD from Methanosarcina barkeri was studied using enzyme variants lacking individual clusters. The purified enzymes were analyzed using UV/Visible absorption and EPR spectroscopy as well as iron/sulfide determinations showing that AhbD from M. barkeri contains two auxiliary [4Fe-4S] clusters. Heme synthase activity assays suggested that the AuxI cluster might be involved in binding the reaction intermediate and both clusters potentially participate in electron transfer. Full article
(This article belongs to the Special Issue Unraveling Mysteries of Heme Metabolism)
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13 pages, 2921 KiB  
Article
Shapes and Patterns of Heme-Binding Motifs in Mammalian Heme-Binding Proteins
by Dhruv C. Rathod, Sonali M. Vaidya, Marie-T. Hopp, Toni Kühl and Diana Imhof
Biomolecules 2023, 13(7), 1031; https://doi.org/10.3390/biom13071031 - 23 Jun 2023
Cited by 4 | Viewed by 2220
Abstract
Heme is a double-edged sword. On the one hand, it has a pivotal role as a prosthetic group of hemoproteins in many biological processes ranging from oxygen transport and storage to miRNA processing. On the other hand, heme can transiently associate with proteins, [...] Read more.
Heme is a double-edged sword. On the one hand, it has a pivotal role as a prosthetic group of hemoproteins in many biological processes ranging from oxygen transport and storage to miRNA processing. On the other hand, heme can transiently associate with proteins, thereby regulating biochemical pathways. During hemolysis, excess heme, which is released into the plasma, can bind to proteins and regulate their activity and function. The role of heme in these processes is under-investigated, with one problem being the lack of knowledge concerning recognition mechanisms for the initial association of heme with the target protein and the formation of the resulting complex. A specific heme-binding sequence motif is a prerequisite for such complex formation. Although numerous short signature sequences indicating a particular protein function are known, a comprehensive analysis of the heme-binding motifs (HBMs) which have been identified in proteins, concerning specific patterns and structural peculiarities, is missing. In this report, we focus on the evaluation of known mammalian heme-regulated proteins concerning specific recognition and structural patterns in their HBMs. The Cys-Pro dipeptide motifs are particularly emphasized because of their more frequent occurrence. This analysis presents a comparative insight into the sequence and structural anomalies observed during transient heme binding, and consequently, in the regulation of the relevant protein. Full article
(This article belongs to the Special Issue Unraveling Mysteries of Heme Metabolism)
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12 pages, 2206 KiB  
Article
Reactivity of Coproheme Decarboxylase with Monovinyl, Monopropionate Deuteroheme
by Gaurav Patil, Hanna Michlits, Paul G. Furtmüller and Stefan Hofbauer
Biomolecules 2023, 13(6), 946; https://doi.org/10.3390/biom13060946 - 06 Jun 2023
Viewed by 1361
Abstract
Coproheme decarboxylases (ChdCs) are terminal enzymes of the coproporphyrin-dependent heme biosynthetic pathway. In this reaction, two propionate groups are cleaved from the redox-active iron-containing substrate, coproheme, to form vinyl groups of the heme b product. The two decarboxylation reactions proceed sequentially, and a [...] Read more.
Coproheme decarboxylases (ChdCs) are terminal enzymes of the coproporphyrin-dependent heme biosynthetic pathway. In this reaction, two propionate groups are cleaved from the redox-active iron-containing substrate, coproheme, to form vinyl groups of the heme b product. The two decarboxylation reactions proceed sequentially, and a redox-active three-propionate porphyrin, called monovinyl, monopropionate deuteroheme (MMD), is transiently formed as an intermediate. While the reaction mechanism for the first part of the redox reaction, which is initiated by hydrogen peroxide, has been elucidated in some detail, the second part of this reaction, starting from MMD, has not been studied. Here, we report the optimization of enzymatic MMD production by ChdC and purification by reversed-phase chromatography. With the obtained MMD, we were able to study the second part of heme b formation by actinobacterial ChdC from Corynebacterium diphtheriae, starting with Compound I formation upon the addition of hydrogen peroxide. The results indicate that the second part of the decarboxylation reaction is analogous to the first part, although somewhat slower, which is explained by differences in the active site architecture and its H-bonding network. The results are discussed in terms of known kinetic and structural data and help to fill some mechanistic gaps in the overall reaction catalyzed by ChdCs. Full article
(This article belongs to the Special Issue Unraveling Mysteries of Heme Metabolism)
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Review

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16 pages, 1705 KiB  
Review
Neuroprotective Roles of the Biliverdin Reductase-A/Bilirubin Axis in the Brain
by Bindu D. Paul and Andrew A. Pieper
Biomolecules 2024, 14(2), 155; https://doi.org/10.3390/biom14020155 - 28 Jan 2024
Viewed by 908
Abstract
Biliverdin reductase-A (BVRA) is a multi-functional enzyme with a multitude of important roles in physiologic redox homeostasis. Classically, BVRA is well known for converting the heme metabolite biliverdin to bilirubin, which is a potent antioxidant in both the periphery and the brain. However, [...] Read more.
Biliverdin reductase-A (BVRA) is a multi-functional enzyme with a multitude of important roles in physiologic redox homeostasis. Classically, BVRA is well known for converting the heme metabolite biliverdin to bilirubin, which is a potent antioxidant in both the periphery and the brain. However, BVRA additionally participates in many neuroprotective signaling cascades in the brain that preserve cognition. Here, we review the neuroprotective roles of BVRA and bilirubin in the brain, which together constitute a BVRA/bilirubin axis that influences healthy aging and cognitive function. Full article
(This article belongs to the Special Issue Unraveling Mysteries of Heme Metabolism)
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13 pages, 1202 KiB  
Review
Notes from the Underground: Heme Homeostasis in C. elegans
by Caiyong Chen and Iqbal Hamza
Biomolecules 2023, 13(7), 1149; https://doi.org/10.3390/biom13071149 - 19 Jul 2023
Cited by 1 | Viewed by 1454
Abstract
Heme is an iron-containing tetrapyrrole that plays a critical role in various biological processes, including oxygen transport, electron transport, signal transduction, and catalysis. However, free heme is hydrophobic and potentially toxic to cells. Organisms have evolved specific pathways to safely transport this essential [...] Read more.
Heme is an iron-containing tetrapyrrole that plays a critical role in various biological processes, including oxygen transport, electron transport, signal transduction, and catalysis. However, free heme is hydrophobic and potentially toxic to cells. Organisms have evolved specific pathways to safely transport this essential but toxic macrocycle within and between cells. The bacterivorous soil-dwelling nematode Caenorhabditis elegans is a powerful animal model for studying heme-trafficking pathways, as it lacks the ability to synthesize heme but instead relies on specialized trafficking pathways to acquire, distribute, and utilize heme. Over the past 15 years, studies on this microscopic animal have led to the identification of a number of heme-trafficking proteins, with corresponding functional homologs in vertebrates. In this review, we provide a comprehensive overview of the heme-trafficking proteins identified in C. elegans and their corresponding homologs in related organisms. Full article
(This article belongs to the Special Issue Unraveling Mysteries of Heme Metabolism)
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