-
Journal of Inorganic Biochemistry Jul 2023Since their initial discovery some 30 years ago, heme-based O sensors have been extensively studied. Among many other lessons, we have learned that they have adapted a...
Since their initial discovery some 30 years ago, heme-based O sensors have been extensively studied. Among many other lessons, we have learned that they have adapted a wide variety of folds to bind heme for O sensing, and they can couple those sensory domains to transducer domains with many different activities. There is no question that we have learned a great deal about those systems by solving X-ray structures of the truncated pieces of larger multi-domain proteins. All of the studies have, for example, hinted at the importance of protein residues, which were further investigated, usually by site-directed mutagenesis of the full-length proteins together with physico-chemical measurements and enzymatic studies. The biochemistry has suggested that the sensing functions of heme-based O sensors involve not only the entire proteins but also, and quite often, their associated regulatory partners and targets. Here we critically examine the state of knowledge for some well-studied sensors and discuss outstanding questions regarding their structures. For the near future, we may foresee many large complexes with sensor proteins being solved by cryo-EM, to enhance our understanding of their mechanisms.
Topics: Heme; Oxygen; Hemeproteins; Bacterial Proteins
PubMed: 37088047
DOI: 10.1016/j.jinorgbio.2023.112229 -
International Journal of Molecular... Apr 2023Renal immune injury is a frequent cause of end-stage renal disease, and, despite the progress made in understanding underlying pathogenetic mechanisms, current... (Review)
Review
Renal immune injury is a frequent cause of end-stage renal disease, and, despite the progress made in understanding underlying pathogenetic mechanisms, current treatments to preserve renal function continue to be based mainly on systemic immunosuppression. Small molecules, naturally occurring biologic agents, show considerable promise in acting as disease modifiers and may provide novel therapeutic leads. Certain naturally occurring or synthetic Metalloporphyrins (Mps) can act as disease modifiers by increasing heme oxygenase (HO) enzymatic activity and/or synthesis of the inducible HO isoform (HO-1). Depending on the metal moiety of the Mp employed, these effects may occur in tandem or can be discordant (increased HO-1 synthesis but inhibition of enzyme activity). This review discusses effects of Mps, with varying redox-active transitional metals and cyclic porphyrin cores, on mechanisms underlying pathogenesis and outcomes of renal immune injury.
Topics: Heme Oxygenase (Decyclizing); Metalloporphyrins; Heme Oxygenase-1; Kidney
PubMed: 37047787
DOI: 10.3390/ijms24076815 -
Chemico-biological Interactions Feb 2020Carbon monoxide (CO) is an inorganic chemical compound that can bind with hemoglobin with highly toxic effects. In living organisms, it is produced endogenously during... (Review)
Review
Carbon monoxide (CO) is an inorganic chemical compound that can bind with hemoglobin with highly toxic effects. In living organisms, it is produced endogenously during the degradation of heme by oxygenase, which occurs in three isoforms: HO-1, HO-2 and HO-3. CO can play an important role in the regulation of many physiological functions. Carbon Oxide Releasing Molecules (CORMs) are a novel group of chemical compounds capable of controlled CO release directly in tissues or organs. This release depends on concentration, pH, solvent type and temperature. The biological role and the therapeutic potential of different CORMs is not always well demonstrated. However, this mini review summarizes the various function of these compounds.
Topics: Animals; Carbon Monoxide; Heme; Heme Oxygenase (Decyclizing); Isoenzymes
PubMed: 32035862
DOI: 10.1016/j.cbi.2020.108973 -
The Journal of Pharmacology and... Apr 2021Oxidative stress plays a crucial role in the pathogenesis of Parkinson disease (PD), and one strategy for neuroprotective therapy for PD is to scavenge reactive species...
Oxidative stress plays a crucial role in the pathogenesis of Parkinson disease (PD), and one strategy for neuroprotective therapy for PD is to scavenge reactive species using a catalytic antioxidant. Previous studies in our laboratory revealed that pretreatment of lipophilic metalloporphyrins showed protective effects in a mouse PD model. In this study, we optimized the formulations of these metalloporphyrins to deliver them orally and tested their efficacy on disease outcomes in a second species after initiation of an insult (i.e., disease modification). In this study, a pharmaceutical formulation of two metalloporphyrin catalytic antioxidants, AEOL11207 and AEOL11114, was tested for oral drug delivery. Both compounds showed gastrointestinal absorption, achieved high plasma concentrations, and readily penetrated the blood-brain barrier after intravenous or oral delivery. AEOL11207 and AEOL11114 bioavailabilities were calculated to be 24% and 25%, respectively, at a dose of 10 mg/kg via the oral route. In addition, both compounds significantly attenuated 6-hydroxydopamine (6-OHDA)-induced neurotoxic damage, including dopamine depletion, cytokine production, and microglial activation in the striata; dopaminergic neuronal loss in the substantia nigra; oxidative/nitrative stress indices (glutathione disulfide and 3-nitrotyrosine) in the ventral midbrain; and rotation behavioral abnormality in rats. These results indicate that AEOL11207 and AEOL11114 are orally active metalloporphyrins and protect against 6-OHDA neurotoxicity 1-3 days postlesioning, suggesting disease-modifying properties and translational potential for PD. SIGNIFICANCE STATEMENT: Two catalytic antioxidants showed gastrointestinal absorption, achieved high plasma concentrations, and readily penetrated the blood-brain barrier. Both compounds significantly attenuated dopamine depletion, cytokine production, microglial activation, dopaminergic neuronal loss, oxidative/nitrative stress indices, and behavioral abnormality in a Parkinson disease rat model. The results suggest that both metalloporphyrins possess disease-modifying properties that may be useful in treating Parkinson disease.
Topics: Administration, Oral; Animals; Antioxidants; Blood-Brain Barrier; Male; Metalloporphyrins; Neuroprotective Agents; Parkinsonian Disorders; Rats; Rats, Sprague-Dawley; Tissue Distribution
PubMed: 33500265
DOI: 10.1124/jpet.120.000229 -
Journal of the American Chemical Society Oct 2022Selective functionalization of aliphatic C-H bonds, ubiquitous in molecular structures, could allow ready access to diverse chemical products. While enzymatic...
Selective functionalization of aliphatic C-H bonds, ubiquitous in molecular structures, could allow ready access to diverse chemical products. While enzymatic oxygenation of C-H bonds is well established, the analogous enzymatic nitrogen functionalization is still unknown; nature is reliant on preoxidized compounds for nitrogen incorporation. Likewise, synthetic methods for selective nitrogen derivatization of unbiased C-H bonds remain elusive. In this work, new-to-nature heme-containing nitrene transferases were used as starting points for the directed evolution of enzymes to selectively aminate and amidate unactivated C(sp)-H sites. The desymmetrization of methyl- and ethylcyclohexane with divergent site selectivity is offered as demonstration. The evolved enzymes in these lineages are highly promiscuous and show activity toward a wide array of substrates, providing a foundation for further evolution of nitrene transferase function. Computational studies and kinetic isotope effects (KIEs) are consistent with a stepwise radical pathway involving an irreversible, enantiodetermining hydrogen atom transfer (HAT), followed by a lower-barrier diastereoselectivity-determining radical rebound step. In-enzyme molecular dynamics (MD) simulations reveal a predominantly hydrophobic pocket with favorable dispersion interactions with the substrate. By offering a direct path from saturated precursors, these enzymes present a new biochemical logic for accessing nitrogen-containing compounds.
Topics: Nitrogen; Catalysis; Hydrogen; Heme; Transferases
PubMed: 36194202
DOI: 10.1021/jacs.2c08285 -
Stem Cells and Development Jun 2023Intracerebral hemorrhage (ICH) is a common subtype of stroke with a very high mortality rate, but there is still no effective cure. Increasing evidence suggests that...
Intracerebral hemorrhage (ICH) is a common subtype of stroke with a very high mortality rate, but there is still no effective cure. Increasing evidence suggests that heme accumulation and neuronal ferroptosis play an important role in secondary injury after ICH. Neural stem cells (NSCs), as seed cells of the central nervous system, have received much attention due to their abundant paracrine product components and low immunogenicity. In this study, we focused on the protective mechanism of neural stem cell secretome (NSC-S) against neuronal ferroptosis in an ICH mouse model using hemin-induced in vitro models and collagenase type IV-induced in vivo models. The results showed that NSC-S could ameliorate neurological deficits and reduce neuronal injury in ICH model mice. In addition, NSC-S reduced heme uptake and ferroptosis in hemin-treated N2a cells in vitro. NSC-S induced the activation of Nrf-2 signaling pathway. However, these effects of NSC-S were abolished by the Nrf-2 inhibitor ML385. Notably, HSPE1 in NSC-S may be associated with the protection of NSC-S against hemin-injured neurons via the Nrf-2 signaling pathway. In summary, NSC-S protects against secondary neuronal injury in ICH via the Nrf-2 signaling pathway. Also, this functionality may be implemented by HSPE1.
Topics: Humans; Mice; Animals; Ferroptosis; Heme; Hemin; Secretome; Cerebral Hemorrhage; Neural Stem Cells; Neurons; Signal Transduction
PubMed: 36960702
DOI: 10.1089/scd.2023.0010 -
Quarterly Reviews of Biophysics Jan 2023Ferric heme (= ferric protoporphyrin IX = hemin) is an important prosthetic group of different types of enzymes, including the intensively investigated and widely... (Review)
Review
Ferric heme (= ferric protoporphyrin IX = hemin) is an important prosthetic group of different types of enzymes, including the intensively investigated and widely applied horseradish peroxidase (HRP). In HRP, hemin is present in monomeric form in a hydrophobic pocket containing among other amino acid side chains the two imidazoyl groups of His170 and His42. Both amino acids are important for the peroxidase activity of HRP as an axial ligand of hemin (proximal His170) and as an acid/base catalyst (distal His42). A key feature of the peroxidase mechanism of HRP is the initial formation of compound I under heterolytic cleavage of added hydrogen peroxide as a terminal oxidant. Investigations of free hemin dispersed in aqueous solution showed that different types of hemin dimers can form, depending on the experimental conditions, possibly resulting in hemin crystallization. Although it has been recognized already in the 1970s that hemin aggregation can be prevented in aqueous solution by using micelle-forming amphiphiles, it remains a challenge to prepare hemin-containing micellar and vesicular systems with peroxidase-like activities. Such systems are of interest as cheap HRP-mimicking catalysts for analytical and synthetic applications. Some of the key concepts on which research in this fascinating and interdisciplinary field is based are summarized, along with major accomplishments and possible directions for further improvement. A systematic analysis of the physico-chemical properties of hemin in aqueous micellar solutions and vesicular dispersions must be combined with a reliable evaluation of its catalytic activity. Future studies should show how well the molecular complexity around hemin in HRP can be mimicked by using micelles or vesicles. Because of the importance of heme in virtually all biological systems and the fact that porphyrins and hemes can be obtained under potentially prebiotic conditions, ideas exist about the possible role of heme-containing micellar and vesicular systems in prebiotic times.
Topics: Heme; Hemin; Micelles; Horseradish Peroxidase; Peroxidases; Iron; Iron, Dietary; Amino Acids
PubMed: 36628454
DOI: 10.1017/S0033583522000130 -
Optics Express Feb 2024Heme is the prosthetic group for cytochrome that exists in nearly all living organisms and serves as a vital component of human red blood cells (RBCs). Tunable optical...
Heme is the prosthetic group for cytochrome that exists in nearly all living organisms and serves as a vital component of human red blood cells (RBCs). Tunable optical nonlinearity in suspensions of RBCs has been demonstrated previously, however, the nonlinear optical response of a pure heme (without membrane structure) solution has not been studied to our knowledge. In this work, we show optical nonlinearity in two common kinds of heme (i.e., hemin and hematin) solutions by a series of experiments and numerical simulations. We find that the mechanism of nonlinearity in heme solutions is distinct from that observed in the RBC suspensions where the nonlinearity can be easily tuned through optical power, concentration, and the solution properties. In particular, we observe an unusual phenomenon wherein the heme solution exhibits negative optical nonlinearity and render self-collimation of a focused beam at specific optical powers, enabling shape-preserving propagation of light to long distances. Our results may have potential applications in optical imaging and medical diagnosis through blood.
Topics: Humans; Heme; Erythrocytes; Optical Imaging
PubMed: 38439294
DOI: 10.1364/OE.510714 -
The mitochondrial heme metabolon: Insights into the complex(ity) of heme synthesis and distribution.Molecular Genetics and Metabolism Nov 2019Heme is an essential cofactor in metazoans that is also toxic in its free state. Heme is synthesized by most metazoans and must be delivered to all cellular compartments... (Review)
Review
Heme is an essential cofactor in metazoans that is also toxic in its free state. Heme is synthesized by most metazoans and must be delivered to all cellular compartments for incorporation into a variety of hemoproteins. The heme biosynthesis enzymes have been proposed to exist in a metabolon, a protein complex consisting of interacting enzymes in a metabolic pathway. Metabolons enhance the function of enzymatic pathways by creating favorable microenvironments for pathway enzymes and intermediates, facilitating substrate transport, and providing a scaffold for interactions with other pathways, signaling molecules, or organelles. Herein we detail growing evidence for a mitochondrial heme metabolon and discuss its implications for the study of heme biosynthesis and cellular heme homeostasis.
Topics: Animals; Heme; Homeostasis; Humans; Metabolic Networks and Pathways; Metabolome; Mice; Mitochondria
PubMed: 30709775
DOI: 10.1016/j.ymgme.2019.01.006 -
Scientific Reports Sep 2023Soy leghemoglobin is one of the most important and key ingredients in plant-based meat substitutes that can imitate the colour and flavour of the meat. To improve the...
Soy leghemoglobin is one of the most important and key ingredients in plant-based meat substitutes that can imitate the colour and flavour of the meat. To improve the high-yield production of leghemoglobin protein and its main component-heme in the yeast Pichia pastoris, glycerol and methanol cultivation conditions were studied. Additionally, in-silico metabolic modelling analysis of growth-coupled enzyme quantity, suggests metabolic gene up/down-regulation strategies for heme production. First, cultivations and metabolic modelling analysis of P. pastoris were performed on glycerol and methanol in different growth media. Glycerol cultivation uptake and production rates can be increased by 50% according to metabolic modelling results, but methanol cultivation-is near the theoretical maximum. Growth-coupled metabolic optimisation results revealed the best feasible upregulation (33 reactions) (1.47% of total reactions) and 66 downregulation/deletion (2.98% of total) reaction suggestions. Finally, we describe reaction regulation suggestions with the highest potential to increase heme production yields.
Topics: Glycerol; Leghemoglobin; Methanol; Heme
PubMed: 37739976
DOI: 10.1038/s41598-023-42865-w