Journal articles: 'Functional Modeling - Heme Enzymes'

1

Timmins, Amy, and Sam P. de Visser. "A Comparative Review on the Catalytic Mechanism of Nonheme Iron Hydroxylases and Halogenases." Catalysts 8, no. 8 (July 31, 2018): 314. http://dx.doi.org/10.3390/catal8080314.

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Enzymatic halogenation and haloperoxidation are unusual processes in biology; however, a range of halogenases and haloperoxidases exist that are able to transfer an aliphatic or aromatic C–H bond into C–Cl/C–Br. Haloperoxidases utilize hydrogen peroxide, and in a reaction with halides (Cl−/Br−), they react to form hypohalides (OCl−/OBr−) that subsequently react with substrate by halide transfer. There are three types of haloperoxidases, namely the iron-heme, nonheme vanadium, and flavin-dependent haloperoxidases that are reviewed here. In addition, there are the nonheme iron halogenases that show structural and functional similarity to the nonheme iron hydroxylases and form an iron(IV)-oxo active species from a reaction of molecular oxygen with α-ketoglutarate on an iron(II) center. They subsequently transfer a halide (Cl−/Br−) to an aliphatic C–H bond. We review the mechanism and function of nonheme iron halogenases and hydroxylases and show recent computational modelling studies of our group on the hectochlorin biosynthesis enzyme and prolyl-4-hydroxylase as examples of nonheme iron halogenases and hydroxylases. These studies have established the catalytic mechanism of these enzymes and show the importance of substrate and oxidant positioning on the stereo-, chemo- and regioselectivity of the reaction that takes place.

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Robins, Tiina, Jonas Carlsson, Maria Sunnerhagen, Anna Wedell, and Bengt Persson. "Molecular Model of Human CYP21 Based on Mammalian CYP2C5: Structural Features Correlate with Clinical Severity of Mutations Causing Congenital Adrenal Hyperplasia." Molecular Endocrinology 20, no. 11 (November 1, 2006): 2946–64. http://dx.doi.org/10.1210/me.2006-0172.

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Abstract Enhanced understanding of structure-function relationships of human 21-hydroxylase, CYP21, is required to better understand the molecular causes of congenital adrenal hyperplasia. To this end, a structural model of human CYP21 was calculated based on the crystal structure of rabbit CYP2C5. All but two known allelic variants of missense type, a total of 60 disease-causing mutations and six normal variants, were analyzed using this model. A structural explanation for the corresponding phenotype was found for all but two mutants for which available clinical data are also discrepant with in vitro enzyme activity. Calculations of protein stability of modeled mutants were found to correlate inversely with the corresponding clinical severity. Putative structurally important residues were identified to be involved in heme and substrate binding, redox partner interaction, and enzyme catalysis using docking calculations and analysis of structurally determined homologous cytochrome P450s (CYPs). Functional and structural consequences of seven novel mutations, V139E, C147R, R233G, T295N, L308F, R366C, and M473I, detected in Scandinavian patients with suspected congenital adrenal hyperplasia of different severity, were predicted using molecular modeling. Structural features deduced from the models are in good correlation with clinical severity of CYP21 mutants, which shows the applicability of a modeling approach in assessment of new CYP21 mutations.

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Krone, Nils, Yulia Grischuk, Marina Müller, Ruth Elisabeth Volk, Joachim Grötzinger, Paul-Martin Holterhus, Wolfgang G. Sippell, and Felix G. Riepe. "Analyzing the Functional and Structural Consequences of Two Point Mutations (P94L and A368D) in the CYP11B1 Gene Causing Congenital Adrenal Hyperplasia Resulting from 11-Hydroxylase Deficiency." Journal of Clinical Endocrinology & Metabolism 91, no. 7 (July 1, 2006): 2682–88. http://dx.doi.org/10.1210/jc.2006-0209.

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Abstract Context: Congenital adrenal hyperplasia is a group of autosomal recessive inherited disorders of steroidogenesis. The deficiency of steroid 11-hydroxylase (CYP11B1) resulting from mutations in the CYP11B1 gene is the second most frequent cause. Objective: We studied the functional and structural consequences of two CYP11B1 missense mutations, which were detected in a 1.8-yr-old boy with acne and precocious pseudopuberty, to prove their clinical relevance and study their impact on CYP11B1 function. Results: The in vitro expression studies in COS-7 cells revealed an almost complete absence of CYP11B1 activity for the P94L mutant to 0.05% for the conversion of 11-deoxycortisol to cortisol. The A368D mutant severely reduced the CYP11B1 enzymatic activity to 1.17%. Intracellular localization studies by immunofluorescence revealed that the mutants were correctly localized. Introducing these mutations in a three-dimensional model structure of the CYP11B1 protein provides a possible explanation for the effects measured in vitro. We hypothesize that the A368D mutation interferes with structures important for substrate specificity and heme iron binding, thus explaining its major functional impact. However, according to structural analysis, we would expect only a minor effect of the P94L mutant on 11-hydroxylase activity, which contrasts with the observed major effect of this mutation both in vitro and in vivo. Conclusion: Analyzing the in vitro enzyme function is a complementary procedure to genotyping and a valuable tool for understanding the clinical phenotype of 11-hydroxylase deficiency. This is the basis for accurate genetic counseling, prenatal diagnosis, and treatment. Moreover, the combination of in vitro enzyme function and molecular modeling provides valuable insights in cytochrome P450 structural-functional relationships, although one must be aware of the limitations of in silico-based methods.

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Fontecave, M., S. Ménage, and C. Duboc-Toia. "Functional models of non-heme diiron enzymes." Coordination Chemistry Reviews 178-180 (December 1998): 1555–72. http://dx.doi.org/10.1016/s0010-8545(98)00119-2.

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5

Shteinman, A. A. "Structural-functional modeling of non-heme oxygenases." Russian Chemical Bulletin 60, no. 7 (July 2011): 1290–300. http://dx.doi.org/10.1007/s11172-011-0197-5.

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Yadav, Rahul, and Emily E. Scott. "Endogenous insertion of non-native metalloporphyrins into human membrane cytochrome P450 enzymes." Journal of Biological Chemistry 293, no. 43 (September 14, 2018): 16623–34. http://dx.doi.org/10.1074/jbc.ra118.005417.

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Human cytochrome P450 enzymes are membrane-bound heme-containing monooxygenases. As is the case for many heme-containing enzymes, substitution of the metal in the center of the heme can be useful for mechanistic and structural studies of P450 enzymes. For many heme proteins, the iron protoporphyrin prosthetic group can be extracted and replaced with protoporphyrin containing another metal, but human membrane P450 enzymes are not stable enough for this approach. The method reported herein was developed to endogenously produce human membrane P450 proteins with a nonnative metal in the heme. This approach involved coexpression of the P450 of interest, a heme uptake system, and a chaperone in Escherichia coli growing in iron-depleted minimal medium supplemented with the desired trans-metallated protoporphyrin. Using the steroidogenic P450 enzymes CYP17A1 and CYP21A2 and the drug-metabolizing CYP3A4, we demonstrate that this approach can be used with several human P450 enzymes and several different metals, resulting in fully folded proteins appropriate for mechanistic, functional, and structural studies including solution NMR.

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Nemukhin, A. V., B. L. Grigorenko, I. A. Topol, and S. K. Burt. "Modeling dioxygen binding to the non-heme iron-containing enzymes." International Journal of Quantum Chemistry 106, no. 10 (2006): 2184–90. http://dx.doi.org/10.1002/qua.20910.

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8

Boynton, Tye O., Svetlana Gerdes, Sarah H. Craven, Ellen L. Neidle, John D. Phillips, and Harry A. Dailey. "Discovery of a Gene Involved in a Third Bacterial Protoporphyrinogen Oxidase Activity through Comparative Genomic Analysis and Functional Complementation." Applied and Environmental Microbiology 77, no. 14 (June 3, 2011): 4795–801. http://dx.doi.org/10.1128/aem.00171-11.

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ABSTRACTTetrapyrroles are ubiquitous molecules in nearly all living organisms. Heme, an iron-containing tetrapyrrole, is widely distributed in nature, including most characterized aerobic and facultative bacteria. A large majority of bacteria that contain heme possess the ability to synthesize it. Despite this capability and the fact that the biosynthetic pathway has been well studied, enzymes catalyzing at least three steps have remained “missing” in many bacteria. In the current work, we have employed comparative genomics via the SEED genomic platform, coupled with experimental verification utilizingAcinetobacter baylyiADP1, to identify one of the missing enzymes, a new protoporphyrinogen oxidase, the penultimate enzyme in heme biosynthesis. COG1981 was identified by genomic analysis as a candidate protein family for the missing enzyme in bacteria that lacked HemG or HemY, two known protoporphyrinogen oxidases. The predicted amino acid sequence of COG1981 is unlike those of the known enzymes HemG and HemY, but in some genomes, the gene encoding it is found neighboring other heme biosynthetic genes. When the COG1981 gene was deleted from the genome ofA. baylyi, a bacterium that lacks bothhemGandhemY, the organism became auxotrophic for heme. Cultures accumulated porphyrin intermediates, and crude cell extracts lacked protoporphyrinogen oxidase activity. The heme auxotrophy was rescued by the presence of a plasmid-borne protoporphyrinogen oxidase gene from a number of different organisms, such ashemGfromEscherichia coli,hemYfromMyxococcus xanthus, or the human gene for protoporphyrinogen oxidase.

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9

Kojima, T., T. Amano, Y. Ishii, and Y. Matsuda. "Ruthenium-pyridylamine complexes as functional models of non-heme iron enzymes." Journal of Inorganic Biochemistry 67, no. 1-4 (July 1997): 238. http://dx.doi.org/10.1016/s0162-0134(97)80111-0.

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10

Matsunaga, Isamu, and Yoshitsugu Shiro. "Peroxide-utilizing biocatalysts: structural and functional diversity of heme-containing enzymes." Current Opinion in Chemical Biology 8, no. 2 (April 2004): 127–32. http://dx.doi.org/10.1016/j.cbpa.2004.01.001.

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11

Atteia, Ariane, Robert van Lis, and Samuel I. Beale. "Enzymes of the Heme Biosynthetic Pathway in the Nonphotosynthetic Alga Polytomella sp." Eukaryotic Cell 4, no. 12 (December 2005): 2087–97. http://dx.doi.org/10.1128/ec.4.12.2087-2097.2005.

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ABSTRACT Heme biosynthesis involves a number of enzymatic steps which in eukaryotes take place in different cell compartments. Enzyme compartmentalization differs between photosynthetic and nonphotosynthetic eukaryotes. Here we investigated the structures and subcellular localizations of three enzymes involved in the heme pathway in Polytomella sp., a colorless alga evolutionarily related to the green alga Chlamydomonas reinhardtii. Functional complementation of Escherichia coli mutant strains was used to isolate cDNAs encoding three heme biosynthetic enzymes, glutamate-1-semialdehyde aminotransferase, protoporphyrinogen IX oxidase, and ferrochelatase. All three proteins show highest similarity to their counterparts in photosynthetic organisms, including C. reinhardtii. All three proteins have N-terminal extensions suggestive of intracellular targeting, and immunoblot studies indicate their enrichment in a dense cell fraction that is enriched in amyloplasts. These results suggest that even though the plastids of Polytomella sp. are not photosynthetically active, they are the major site of heme biosynthesis. The presence of a gene for glutamate-1-semialdehyde aminotransferase suggests that Polytomella sp. uses the five-carbon pathway for synthesis of the heme precursor 5-aminolevulinic acid.

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12

Park, Hyunchang, and Dongwhan Lee. "Ligand Taxonomy for Bioinorganic Modeling of Dioxygen‐Activating Non‐Heme Iron Enzymes." Chemistry – A European Journal 26, no. 27 (March 17, 2020): 5916–26. http://dx.doi.org/10.1002/chem.201904975.

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13

Shiro, Yoshitsugu. "Functional Studies on Hemoproteins and Heme-enzymes Based on Their Molecular Structures." Bulletin of Japan Society of Coordination Chemistry 75 (May 31, 2020): 51–56. http://dx.doi.org/10.4019/bjscc.75.51.

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14

Belsare, Ketaki D., Anna Joëlle Ruff, Ronny Martinez, and Ulrich Schwaneberg. "Insights on intermolecular FMN-heme domain interaction and the role of linker length in cytochrome P450cin fusion proteins." Biological Chemistry 401, no. 11 (October 25, 2020): 1249–55. http://dx.doi.org/10.1515/hsz-2020-0134.

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AbstractCytochrome P450s are an important group of enzymes catalyzing hydroxylation, and epoxidations reactions. In this work we describe the characterization of the CinA–CinC fusion enzyme system of a previously reported P450 using genetically fused heme (CinA) and FMN (CinC) enzyme domains from Citrobacter braaki. We observed that mixing individually inactivated heme (-) with FMN (-) domain in the CinA-10aa linker - CinC fusion constructs results in recovered activity and the formation of (2S)-2β-hydroxy,1,8-cineole (174 µM), a similar amount when compared to the fully functional fusion protein (176 µM). We also studied the effect of the fusion linker length in the activity complementation assay. Our results suggests an intermolecular interaction between heme and FMN parts from different CinA–CinC fusion protein similar to proposed mechanisms for P450 BM3 on the other hand, linker length plays a crucial influence on the activity of the fusion constructs. However, complementation assays show that inactive constructs with shorter linker lengths have functional subunits, and that the lack of activity might be due to incorrect interaction between fused enzymes.

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Mirts, Evan N., Igor D. Petrik, Parisa Hosseinzadeh, Mark J. Nilges, and Yi Lu. "A designed heme-[4Fe-4S] metalloenzyme catalyzes sulfite reduction like the native enzyme." Science 361, no. 6407 (September 13, 2018): 1098–101. http://dx.doi.org/10.1126/science.aat8474.

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Multielectron redox reactions often require multicofactor metalloenzymes to facilitate coupled electron and proton movement, but it is challenging to design artificial enzymes to catalyze these important reactions, owing to their structural and functional complexity. We report a designed heteronuclear heme-[4Fe-4S] cofactor in cytochromecperoxidase as a structural and functional model of the enzyme sulfite reductase. The initial model exhibits spectroscopic and ligand-binding properties of the native enzyme, and sulfite reduction activity was improved—through rational tuning of the secondary sphere interactions around the [4Fe-4S] and the substrate-binding sites—to be close to that of the native enzyme. By offering insight into the requirements for a demanding six-electron, seven-proton reaction that has so far eluded synthetic catalysts, this study provides strategies for designing highly functional multicofactor artificial enzymes.

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Ha, Edward H., Raymond Y. N. Ho, James F. Kisiel, and Joan Selverstone Valentine. "Modeling the Reactivity of .alpha.-Ketoglutarate-Dependent Non-Heme Iron(II)-Containing Enzymes." Inorganic Chemistry 34, no. 9 (April 1995): 2265–66. http://dx.doi.org/10.1021/ic00113a002.

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17

Mohammadi, Mahnaz, Fatematossadat Pourseyed Aghaei, Banafsheh Noori, and Esmaeil Pakizeh. "Density Functional Theory modeling of the magnetic susceptibility of heme derivatives." Chemical Physics 527 (November 2019): 110498. http://dx.doi.org/10.1016/j.chemphys.2019.110498.

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18

Badawy, Abdulla A.-B. "Kynurenine Pathway of Tryptophan Metabolism: Regulatory and Functional Aspects." International Journal of Tryptophan Research 10 (January 1, 2017): 117864691769193. http://dx.doi.org/10.1177/1178646917691938.

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Regulatory and functional aspects of the kynurenine (K) pathway (KP) of tryptophan (Trp) degradation are reviewed. The KP accounts for ~95% of dietary Trp degradation, of which 90% is attributed to the hepatic KP. During immune activation, the minor extrahepatic KP plays a more active role. The KP is rate-limited by its first enzyme, Trp 2,3-dioxygenase (TDO), in liver and indoleamine 2,3-dioxygenase (IDO) elsewhere. TDO is regulated by glucocorticoid induction, substrate activation and stabilization by Trp, cofactor activation by heme, and end-product inhibition by reduced nicotinamide adenine dinucleotide (phosphate). IDO is regulated by IFN-γ and other cytokines and by nitric oxide. The KP disposes of excess Trp, controls hepatic heme synthesis and Trp availability for cerebral serotonin synthesis, and produces immunoregulatory and neuroactive metabolites, the B3 “vitamin” nicotinic acid, and oxidized nicotinamide adenine dinucleotide. Various KP enzymes are undermined in disease and are targeted for therapy of conditions ranging from immunological, neurological, and neurodegenerative conditions to cancer.

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LaBella, Frank S. "Cytochrome P450 enzymes: ubiquitous "receptors" for drugs." Canadian Journal of Physiology and Pharmacology 69, no. 8 (August 1, 1991): 1129–32. http://dx.doi.org/10.1139/y91-165.

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Most foreign compounds bind to one or more cytochrome P450 drug-metabolizing isozymes. These heme monooxygenases are most concentrated in the endoplasmic reticulum of liver cells but are present in virtually all biological membranes and in all cells. Some radioligands for known hormone receptors have been found to label, with comparable affinities, specific P450 enzymes. A characteristic feature of P450 enzymes is their broad and overlapping drug specificities, with affinity constants ranging over several orders of magnitude. Because fatty acid derivatives and steroids are endogenous substrates for the P450 enzymes, drugs may interfere with the generation of functional cellular lipids. The functional significance of high-affinity binding of drugs to the oxygenases may, on the one hand, be minimal and reflect extraneous or trivial drug–protein interactions. On the other hand, the drug–P450 union may in other cases mediate the major pharmacological response.Key words: cytochrome P450, radioligand binding, microsomes, sigma receptor, antiestrogen receptor.

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20

Carrasco, Maria C., and Shabnam Hematian. "(Hydr)oxo-bridged heme complexes: From structure to reactivity." Journal of Porphyrins and Phthalocyanines 23, no. 11n12 (December 2019): 1286–307. http://dx.doi.org/10.1142/s1088424619300258.

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Iron–porphyrins ([Formula: see text] hemes) are present throughout the biosphere and perform a wide range of functions, particularly those that involve complex multiple-electron redox processes. Some common heme enzymes involved in these processes include cytochrome P450, heme/copper oxidase or heme/non-heme diiron nitric oxide reductase. Consequently, the (hydr)oxo-bridged heme species have been studied for the important roles that they play in many life processes or for their application for catalysis and preparation of new functional materials. This review encompasses important synthetic, structural and reactivity aspects of the (hydr)oxo-bridged heme constructs that govern their function and application. The properties and reactivity of the bridging (hydr)oxo moieties are directly dictated by the coordination environment of the heme core, the nature and ligation of the second metal center attached to the (hydr)oxo group, the presence or absence of a linker, and the degree of flexibility around that linker within the scaffold. Here, we summarize the structural features of all known (hydr)oxo-bridged heme constructs and use those to categorize and thus, provide a more comprehensive picture of structure–function relationships.

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Arnhold, Jürgen, and Ernst Malle. "Halogenation Activity of Mammalian Heme Peroxidases." Antioxidants 11, no. 5 (April 30, 2022): 890. http://dx.doi.org/10.3390/antiox11050890.

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Mammalian heme peroxidases are fascinating due to their unique peculiarity of oxidizing (pseudo)halides under physiologically relevant conditions. These proteins are able either to incorporate oxidized halides into substrates adjacent to the active site or to generate different oxidized (pseudo)halogenated species, which can take part in multiple (pseudo)halogenation and oxidation reactions with cell and tissue constituents. The present article reviews basic biochemical and redox mechanisms of (pseudo)halogenation activity as well as the physiological role of heme peroxidases. Thyroid peroxidase and peroxidasin are key enzymes for thyroid hormone synthesis and the formation of functional cross-links in collagen IV during basement membrane formation. Special attention is directed to the properties, enzymatic mechanisms, and resulting (pseudo)halogenated products of the immunologically relevant proteins such as myeloperoxidase, eosinophil peroxidase, and lactoperoxidase. The potential role of the (pseudo)halogenated products (hypochlorous acid, hypobromous acid, hypothiocyanite, and cyanate) of these three heme peroxidases is further discussed.

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Kellmann, Ralf, Toby Mills, and Brett A. Neilan. "Functional Modeling and Phylogenetic Distribution of Putative Cylindrospermopsin Biosynthesis Enzymes." Journal of Molecular Evolution 62, no. 3 (February 25, 2006): 267–80. http://dx.doi.org/10.1007/s00239-005-0030-6.

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23

Chance, M., L. Powers, C. Kumar, and B. Chance. "X-ray absorption studies of myoglobin peroxide reveal functional differences between globins and heme enzymes." Biochemistry 25, no. 6 (March 1986): 1259–65. http://dx.doi.org/10.1021/bi00354a010.

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24

Savino, Maria, Claudio Carmine Guida, Maria Nardella, Emanuele Murgo, Bartolomeo Augello, Giuseppe Merla, Salvatore De Cosmo, et al. "Circadian Genes Expression Patterns in Disorders Due to Enzyme Deficiencies in the Heme Biosynthetic Pathway." Biomedicines 10, no. 12 (December 9, 2022): 3198. http://dx.doi.org/10.3390/biomedicines10123198.

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Heme is a member of the porphyrins family of cyclic tetrapyrroles and influences various cell processes and signalling pathways. Enzyme deficiencies in the heme biosynthetic pathway provoke rare human inherited metabolic diseases called porphyrias. Protein levels and activity of enzymes involved in the heme biosynthetic pathway and especially 5′-Aminolevulinate Synthase 1 are featured by 24-h rhythmic oscillations driven by the biological clock. Heme biosynthesis and circadian pathways intermingle with mutual modulatory roles. Notably, heme is a ligand of important cogs of the molecular clockwork, which upon heme binding recruit co-repressors and inhibit the transcription of numerous genes enriching metabolic pathways and encoding functional proteins bringing on crucial cell processes. Herein, we assessed mRNA levels of circadian genes in patients suffering from porphyrias and found several modifications of core clock genes and clock-controlled genes expression, associated with metabolic and electrolytic changes. Overall, our results show an altered expression of circadian genes accompanying heme biosynthesis disorders and confirm the need to deepen the knowledge of the mechanisms through which the alteration of the circadian clock circuitry could take part in determining signs and symptoms of porphyria patients and then again could represent a target for innovative therapeutic strategies.

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Kitanishi, Kenichi, Kazuo Kobayashi, Takeshi Uchida, Koichiro Ishimori, Jotaro Igarashi, and Toru Shimizu. "Identification and Functional and Spectral Characterization of a Globin-coupled Histidine Kinase from Anaeromyxobacter sp. Fw109-5." Journal of Biological Chemistry 286, no. 41 (August 18, 2011): 35522–34. http://dx.doi.org/10.1074/jbc.m111.274811.

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Two-component signal transduction systems regulate numerous important physiological functions in bacteria. In this study we have identified, cloned, overexpressed, and characterized a dimeric full-length heme-bound (heme:protein, 1:1 stoichiometry) globin-coupled histidine kinase (AfGcHK) from Anaeromyxobacter sp. strain Fw109-5 for the first time. The Fe(III), Fe(II)-O2, and Fe(II)-CO complexes of the protein displayed autophosphorylation activity, whereas the Fe(II) complex had no significant activity. A H99A mutant lost heme binding ability, suggesting that this residue is the heme proximal ligand. Moreover, His-183 was proposed as the autophosphorylation site based on the finding that the H183A mutant protein was not phosphorylated. The phosphate group of autophosphorylated AfGcHK was transferred to Asp-52 and Asp-169 of a response regulator, as confirmed from site-directed mutagenesis experiments. Based on the amino acid sequences and crystal structures of other globin-coupled oxygen sensor enzymes, Tyr-45 was assumed to be the O2 binding site at the heme distal side. The O2 dissociation rate constant, 0.10 s−1, was substantially increased up to 8.0 s−1 upon Y45L mutation. The resonance Raman frequencies representing νFe-O2 (559 cm−1) and νO-O (1149 cm−1) of the Fe(II)-O2 complex of Y45F mutant AfGcHK were distinct from those of the wild-type protein (νFe-O2, 557 cm−1; νO-O, 1141 cm−1), supporting the proposal that Tyr-45 is located at the distal side and forms hydrogen bonds with the oxygen molecule bound to the Fe(II) complex. Thus, we have successfully identified and characterized a novel heme-based globin-coupled oxygen sensor histidine kinase, AfGcHK, in this study.

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Konduri, Purna Chaitanya, Tianyuan Wang, Narges Salamat, and Li Zhang. "Heme, A Metabolic Sensor, Directly Regulates the Activity of the KDM4 Histone Demethylase Family and Their Interactions with Partner Proteins." Cells 9, no. 3 (March 22, 2020): 773. http://dx.doi.org/10.3390/cells9030773.

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The KDM4 histone demethylase subfamily is constituted of yeast JmjC domain-containing proteins, such as Gis1, and human Gis1 orthologues, such as KDM4A/B/C. KDM4 proteins have important functions in regulating chromatin structure and gene expression in response to metabolic and nutritional stimuli. Heme acts as a versatile signaling molecule to regulate important cellular functions in diverse organisms ranging from bacteria to humans. Here, using purified KDM4 proteins containing the JmjN/C domain, we showed that heme stimulates the histone demethylase activity of the JmjN/C domains of KDM4A and Cas well as full-length Gis1. Furthermore, we found that the C-terminal regions of KDM4 proteins, like that of Gis1, can confer heme regulation when fused to an unrelated transcriptional activator. Interestingly, biochemical pull-down of Gis1-interacting proteins followed by mass spectrometry identified 147 unique proteins associated with Gis1 under heme-sufficient and/or heme-deficient conditions. These 147 proteins included a significant number of heterocyclic compound-binding proteins, Ubl-conjugated proteins, metabolic enzymes/proteins, and acetylated proteins. These results suggested that KDM4s interact with diverse cellular proteins to form a complex network to sense metabolic and nutritional conditions like heme levels and respond by altering their interactions with other proteins and functional activities, such as histone demethylation.

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Hagadorn, John R., Lawrence Que, and William B. Tolman. "A Bulky Benzoate Ligand for Modeling the Carboxylate-Rich Active Sites of Non-Heme Diiron Enzymes." Journal of the American Chemical Society 120, no. 51 (December 1998): 13531–32. http://dx.doi.org/10.1021/ja983333t.

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Babandi, Abba, Chioma A. Anosike, Lawrence U. S. Ezeanyika, Kemal Yelekçi, and Abdullahi Ibrahim Uba. "Molecular modeling studies of some phytoligands from Ficus sycomorus fraction as potential inhibitors of cytochrome CYP6P3 enzyme of Anopheles coluzzii." Jordan Journal of Pharmaceutical Sciences 15, no. 2 (June 1, 2022): 258–75. http://dx.doi.org/10.35516/jjps.v15i2.324.

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The major obstacle in controlling malaria is the mosquito’s resistance to insecticides, including pyrethroids. The resistance is mainly due to the over-expression of detoxification enzymes such as cytochromes. Insecticides tolerance can be reduced by inhibitors of P450s involved in insecticide detoxification. Here, to design potential CYP6P3 inhibitors, a homology model of the enzyme was constructed using the crystal structure of retinoic acid-bound cyanobacterial CYP120A1 (PDB ID: 2VE3; Resolution: 2.1 Å). Molecular docking study and computational modeling were employed to determine the inhibitory potentials of some phytoligands isolated from Ficus sycomorus against Anopheles coluzzii modeled P450 isoforms, CYP6P3, implicated in resistance. Potential ligand optimization (LE) properties were analyzed using standard mathematical models. Compounds 5, 8,and 9 bound to the Heme iron of CYP6P3 within 3.14, 2.47 and 2.59 Å, respectively. Their respective binding energies were estimated to be -8.93, -10.44, and -12.56 Kcal/mol. To examine the stability of their binding mode, the resulting docking complexes of these compounds with CYP6P3 were subjected to 50 ns MD simulation. The compounds remained bound to the enzyme and Fe (Heme):O (Ligand) distance appeared to be maintained over time. The coordination of a strong ligand to the heme iron shifts the iron from the high- to the stable low-spin form and prevented oxygen from binding to the heme thereby inhibiting the catalytic activity. The LE index showed the high potential of these compounds (5 and 8) to provide a core fragment for optimization into potent P450 inhibitors.

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Park, Kiyoung, and Edward I. Solomon. "Modeling nuclear resonance vibrational spectroscopic data of binuclear nonheme iron enzymes using density functional theory." Canadian Journal of Chemistry 92, no. 10 (October 2014): 975–78. http://dx.doi.org/10.1139/cjc-2014-0067.

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Nuclear resonance vibrational spectroscopy (NRVS) is a powerful technique that can provide geometric structural information on key reaction intermediates of Fe-containing systems when utilized in combination with density functional theory (DFT). However, in the case of binuclear nonheme iron enzymes, DFT-predicted NRVS spectra have been found to be sensitive to the truncation method used to model the active sites of the enzymes. Therefore, in this study various-level truncation schemes have been tested to predict the NRVS spectrum of a binuclear nonheme iron enzyme, and a reasonably sized DFT model that is suitable for employing the NRVS/DFT combined methodology to characterize binuclear nonheme iron enzymes has been developed.

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Siletsky, Sergey A., and Vitaliy B. Borisov. "Proton Pumping and Non-Pumping Terminal Respiratory Oxidases: Active Sites Intermediates of These Molecular Machines and Their Derivatives." International Journal of Molecular Sciences 22, no. 19 (October 7, 2021): 10852. http://dx.doi.org/10.3390/ijms221910852.

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Terminal respiratory oxidases are highly efficient molecular machines. These most important bioenergetic membrane enzymes transform the energy of chemical bonds released during the transfer of electrons along the respiratory chains of eukaryotes and prokaryotes from cytochromes or quinols to molecular oxygen into a transmembrane proton gradient. They participate in regulatory cascades and physiological anti-stress reactions in multicellular organisms. They also allow microorganisms to adapt to low-oxygen conditions, survive in chemically aggressive environments and acquire antibiotic resistance. To date, three-dimensional structures with atomic resolution of members of all major groups of terminal respiratory oxidases, heme-copper oxidases, and bd-type cytochromes, have been obtained. These groups of enzymes have different origins and a wide range of functional significance in cells. At the same time, all of them are united by a catalytic reaction of four-electron reduction in oxygen into water which proceeds without the formation and release of potentially dangerous ROS from active sites. The review analyzes recent structural and functional studies of oxygen reduction intermediates in the active sites of terminal respiratory oxidases, the features of catalytic cycles, and the properties of the active sites of these enzymes.

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Naruta, Yoshinori, Masa-aki Sasayama, and Kanako Ichihara. "Functional modeling of managanese-containing O2 evolution enzymes with managanese porphyrin dimers." Journal of Molecular Catalysis A: Chemical 117, no. 1-3 (March 1997): 115–21. http://dx.doi.org/10.1016/s1381-1169(96)00416-5.

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Majumdar, Amit, and Sabyasachi Sarkar. "Bioinorganic chemistry of molybdenum and tungsten enzymes: A structural–functional modeling approach." Coordination Chemistry Reviews 255, no. 9-10 (May 2011): 1039–54. http://dx.doi.org/10.1016/j.ccr.2010.11.027.

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Wan, Dun, Li Fu Liao, and Ying Wu Lin. "Impacts of Uranyl Ion on the Structure and Function of Cytochrome b₅ His39Ser Mutant." Advanced Materials Research 455-456 (January 2012): 1204–9. http://dx.doi.org/10.4028/www.scientific.net/amr.455-456.1204.

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Uranium is toxic to human body with mechanisms not fully understood. The structural and functional consequences of uranyl ions (UO22+) interacting with an axial mutant of cytochrome b5, His39Ser (cyt b5 H39S), were investigated by both spectroscopic and molecular modeling methods. Although slightly disturbs protein folding, UO22+ binding to cyt b5 H39S leads to a decrease of peroxidase activity. A uranyl binding site was further proposed in the heme-binding domain at Glu37 and Glu43. The impacts of UO22+ binding to cyt b5 H39S studied herein provide valuable insights into the toxicity mechanism of UO22+ towards membrane heme proteins.

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Shumyantseva, Victoria V., Polina I. Koroleva, Tatiana V. Bulko, and Lyubov E. Agafonova. "Alternative Electron Sources for Cytochrome P450s Catalytic Cycle: Biosensing and Biosynthetic Application." Processes 11, no. 6 (June 13, 2023): 1801. http://dx.doi.org/10.3390/pr11061801.

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The functional significance of cytochrome P450s (CYP) enzymes is their ability to catalyze the biotransformation of xenobiotics and endogenous compounds. P450 enzymes catalyze regio- and stereoselective oxidations of C-C and C-H bonds in the presence of oxygen as a cosubstrate. Initiation of cytochrome P450 catalytic cycle needs an electron donor (NADPH, NADH cofactor) in nature or alternative artificial electron donors such as electrodes, peroxides, photo reduction, and construction of enzymatic “galvanic couple”. In our review paper, we described alternative “handmade” electron sources to support cytochrome P450 catalysis. Physical-chemical methods in relation to biomolecules are possible to convert from laboratory to industry and construct P450-bioreactors for practical application. We analyzed electrochemical reactions using modified electrodes as electron donors. Electrode/P450 systems are the most analyzed in terms of the mechanisms underlying P450-catalyzed reactions. Comparative analysis of flat 2D and nanopore 3D electrode modifiers is discussed. Solar-powered photobiocatalysis for CYP systems with photocurrents providing electrons to heme iron of CYP and photoelectrochemical biosensors are also promising alternative light-driven systems. Several examples of artificial “galvanic element” construction using Zn as an electron source for the reduction of Fe3+ ion of heme demonstrated potential application. The characteristics, performance, and potential applications of P450 electrochemical systems are also discussed.

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Tewari, Rajesh Kumar. "Nitric Oxide-Mediated Modulation of Functional Iron Status in Iron-Deficient Maize Plants." INTERNATIONAL JOURNAL OF PLANT AND ENVIRONMENT 5, no. 02 (April 30, 2019): 78–83. http://dx.doi.org/10.18811/ijpen.v5i02.2.

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Nitric oxide is reported to alleviate Fe-deficiency effects, possibly by enhancing the functional Fe status of plants. Study describes changes in leaf tissue Fe status and consequent modulation of oxidative stress and antioxidant defense in Fe-deficient maize (Zea mays L.) plants supplied with NO. Supply of sodium nitroprusside (SNP), but not of sodium ferrocyanide (SF), caused regreening of leaves, syntheses of chlorophylls and carotenoids and increased activities of hydrogen peroxide-scavenging heme-Fe enzymes and lipid peroxidation, decreased SOD activity and hydrogen peroxide concentration. Though SNP or SF appears to donate Fe and increase leaf active Fe, the later did not induce increases in chlorophyll and carotenoids, and therefore NO appears to have a role in Fe nutrition irrespective of total or active Fe status of plants.

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Rondelli, Catherine, Aiden Danoff, Hector Bergonia, Samantha Gillis, Julia Free, John D. Phillips, and Yvette Y. Yien. "Regulation of Erythroid Heme Synthesis By the Mitochondrial Clpx Unfoldase." Blood 134, Supplement_1 (November 13, 2019): 427. http://dx.doi.org/10.1182/blood-2019-132039.

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Differentiating erythroid cells synthesize large quantities of heme for hemoglobinization. While the transcriptional regulation and enzymatic mechanisms of the heme synthetic enzymes are well characterized, we lack mechanistic understanding of how their protein stability, cofactor incorporation and functional interactions with mitochondrial housekeeping proteins are regulated. These mechanisms can rapidly alter the rate of heme synthesis in response to external stimuli and metabolic requirements, and are critical for heme regulation within a tissue-specific and developmental context. CLPX, a mitochondrial protein unfoldase best understood for its function in a proteasome-like enzyme complex with the peptidase CLPP (the CLPXP ATP-dependent protease) plays a central role in regulation of mitochondrial protein turnover, is one such heme regulatory protein. CLPX activates yeast ALAS, which catalyzes the committed step of the heme synthesis pathway, by facilitating the incorporation of its cofactor, PLP, and is required for erythroid heme synthesis in zebrafish (Kardon et al. Cell 2015). Paradoxically, it regulates the turnover of ALAS1 and ALAS2 protein in vertebrate cell lines and appears to regulate the heme synthesis downstream of ALAS (Kubota et al. JBC 2016, Yien et al. PNAS 2017). However, it is not known if vertebrate ALAS was activated by ALAS, or if the requirement for CLPX in vertebrate heme synthesis was caused its regulation of ALAS activity (Figure A). To dissect the roles of CLPX in erythroid heme synthesis, we knocked out Clpxand Clpp in murine erythroleukemia (MEL) cells and assayed the activity, stability, and steady state levels of the heme synthesis enzymes, ALAS2 and FECH, which colocalize with ALAS in the mitochondrial matrix. Consistent with previous observations, Clpx -/- MEL cells had a heme defect, while Clpp -/-cells did not (Figure B). However, in contrast to previous observations in the yeast model, CLPX is not required for ALAS activation in erythroid cells, but plays a key role in regulating ALAS2 turnover in concert with the CLPP peptidase (Figure C). During erythroid differentiation, CLPP protein levels are decreased, stabilizing ALAS2 protein (Figure D). Although differentiating Clpx -/-and Clpp -/- MEL cells did not demonstrate any changes in ALAS2 turnover, likely because steady-state levels of CLPP protein were already decreased (Figure E), we observed an increase in steady-state ALAS2 protein levels and a dramatic increase in ALAS2 enzyme activity. In vitro mitochondrial iron transport/heme synthesis assays revealed a heme defect in Clpx -/-MEL cells, suggesting that CLPX plays a role in mitochondrial iron metabolism. Collectively, these data suggest a complex, differentiation-stage specific regulation of heme synthesis by the CLPXP proteolytic complex (Figure F). As Clpx -/- mouse embryos die by about E9.5 (mousephenotype.org), we dissected the in vivo role of Clpxin erythropoiesis by analyzing the phenotypes of clpxa and clpxb mutant zebrafish obtained from ZIRC. To accomplish this, we crossed clpxa and clpxb mutant zebrafish into Tg(lcr:GFP) zebrafish line in which erythroid cells are fluorescently labeled with GFP (Ganis et al Dev Biol 2012). We observed that clpxa mutant zebrafish had an early erythropoietic defect at 24 hpf that resolved at 48hpf; this developmental defect was not observed in clpxbmutant zebrafish. Benzidine staining of heme in mutant zebrafish revealed that while clpxa was dispensable for erythroid heme synthesis, clpxb was required for erythroid hemoglobinization (Figure G). Lastly, clpxbzebrafish mutants continued to be developmentally delayed and did not survive past 5 dpf. Collectively, our observations in cell lines and in the zebrafish model demonstrate that Clpx is essential for the maintenance of differentiated erythroid cells, as well as for the differentiation of the erythroid lineage. The control of heme synthesis and erythroid development by CLPX reveals how mitochondrial physiology and heme synthesis are interdependent. Our results reveal an important regulatory node where the mitochondrial protein quality control machinery intersects with key steps in heme synthesis. Further, our studies provide important genetic tools for dissecting these regulatory components in isolation as well as within the in vivocontext of erythropoiesis. Figure Disclosures No relevant conflicts of interest to declare.

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Bela, Krisztina, Riyazuddin Riyazuddin, and Jolán Csiszár. "Plant Glutathione Peroxidases: Non-Heme Peroxidases with Large Functional Flexibility as a Core Component of ROS-Processing Mechanisms and Signalling." Antioxidants 11, no. 8 (August 21, 2022): 1624. http://dx.doi.org/10.3390/antiox11081624.

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Glutathione peroxidases (GPXs) are non-heme peroxidases catalyzing the reduction of H2O2 or organic hydroperoxides to water or corresponding alcohols using glutathione (GSH) or thioredoxin (TRX) as a reducing agent. In contrast to animal GPXs, the plant enzymes are non-seleno monomeric proteins that generally utilize TRX more effectively than GSH but can be a putative link between the two main redox systems. Because of the substantial differences compared to non-plant GPXs, use of the GPX-like (GPXL) name was suggested for Arabidopsis enzymes. GPX(L)s not only can protect cells from stress-induced oxidative damages but are crucial components of plant development and growth. Due to fine-tuning the H2O2 metabolism and redox homeostasis, they are involved in the whole life cycle even under normal growth conditions. Significantly new mechanisms were discovered related to their transcriptional, post-transcriptional and post-translational modifications by describing gene regulatory networks, interacting microRNA families, or identifying Lys decrotonylation in enzyme activation. Their involvement in epigenetic mechanisms was evidenced. Detailed genetic, evolutionary, and bio-chemical characterization, and comparison of the main functions of GPXs, demonstrated their species-specific roles. The multisided involvement of GPX(L)s in the regulation of the entire plant life ensure that their significance will be more widely recognized and applied in the future.

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Acerbi, Enzo, Marcela Hortova-Kohoutkova, Tsokyi Choera, Nancy Keller, Jan Fric, Fabio Stella, Luigina Romani, and Teresa Zelante. "Modeling Approaches Reveal New Regulatory Networks in Aspergillus fumigatus Metabolism." Journal of Fungi 6, no. 3 (July 14, 2020): 108. http://dx.doi.org/10.3390/jof6030108.

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Systems biology approaches are extensively used to model and reverse-engineer gene regulatory networks from experimental data. Indoleamine 2,3-dioxygenases (IDOs)—belonging in the heme dioxygenase family—degrade l-tryptophan to kynurenines. These enzymes are also responsible for the de novo synthesis of nicotinamide adenine dinucleotide (NAD+). As such, they are expressed by a variety of species, including fungi. Interestingly, Aspergillus may degrade l-tryptophan not only via IDO but also via alternative pathways. Deciphering the molecular interactions regulating tryptophan metabolism is particularly critical for novel drug target discovery designed to control pathogen determinants in invasive infections. Using continuous time Bayesian networks over a time-course gene expression dataset, we inferred the global regulatory network controlling l-tryptophan metabolism. The method unravels a possible novel approach to target fungal virulence factors during infection. Furthermore, this study represents the first application of continuous-time Bayesian networks as a gene network reconstruction method in Aspergillus metabolism. The experiment showed that the applied computational approach may improve the understanding of metabolic networks over traditional pathways.

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Satarug, Soisungwan, David A. Vesey, and Glenda C. Gobe. "Mitigation of Cadmium Toxicity through Modulation of the Frontline Cellular Stress Response." Stresses 2, no. 3 (September 15, 2022): 355–72. http://dx.doi.org/10.3390/stresses2030025.

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Cadmium (Cd) is an environmental toxicant of public health significance worldwide. Diet is the main Cd exposure source in the non-occupationally exposed and non-smoking populations. Metal transporters for iron (Fe), zinc (Zn), calcium (Ca), and manganese (Mn) are involved in the assimilation and distribution of Cd to cells throughout the body. Due to an extremely slow elimination rate, most Cd is retained by cells, where it exerts toxicity through its interaction with sulfur-containing ligands, notably the thiol (-SH) functional group of cysteine, glutathione, and many Zn-dependent enzymes and transcription factors. The simultaneous induction of heme oxygenase-1 and the metal-binding protein metallothionein by Cd adversely affected the cellular redox state and caused the dysregulation of Fe, Zn, and copper. Experimental data indicate that Cd causes mitochondrial dysfunction via disrupting the metal homeostasis of this organelle. The present review focuses on the adverse metabolic outcomes of chronic exposure to low-dose Cd. Current epidemiologic data indicate that chronic exposure to Cd raises the risk of type 2 diabetes by several mechanisms, such as increased oxidative stress, inflammation, adipose tissue dysfunction, increased insulin resistance, and dysregulated cellular intermediary metabolism. The cellular stress response mechanisms involving the catabolism of heme, mediated by heme oxygenase-1 and -2 (HO-1 and HO-2), may mitigate the cytotoxicity of Cd. The products of their physiologic heme degradation, bilirubin and carbon monoxide, have antioxidative, anti-inflammatory, and anti-apoptotic properties.

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Rovaletti, Anna, Luca De Gioia, Piercarlo Fantucci, Claudio Greco, Jacopo Vertemara, Giuseppe Zampella, Federica Arrigoni, and Luca Bertini. "Recent Theoretical Insights into the Oxidative Degradation of Biopolymers and Plastics by Metalloenzymes." International Journal of Molecular Sciences 24, no. 7 (March 28, 2023): 6368. http://dx.doi.org/10.3390/ijms24076368.

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Molecular modeling techniques have become indispensable in many fields of molecular sciences in which the details related to mechanisms and reactivity need to be studied at an atomistic level. This review article provides a collection of computational modeling works on a topic of enormous interest and urgent relevance: the properties of metalloenzymes involved in the degradation and valorization of natural biopolymers and synthetic plastics on the basis of both circular biofuel production and bioremediation strategies. In particular, we will focus on lytic polysaccharide monooxygenase, laccases, and various heme peroxidases involved in the processing of polysaccharides, lignins, rubbers, and some synthetic polymers. Special attention will be dedicated to the interaction between these enzymes and their substrate studied at different levels of theory, starting from classical molecular docking and molecular dynamics techniques up to techniques based on quantum chemistry.

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Barreiro, Esther, Alain S. Comtois, Shawn Mohammed, Larry C. Lands, and Sabah N. A. Hussain. "Role of heme oxygenases in sepsis-induced diaphragmatic contractile dysfunction and oxidative stress." American Journal of Physiology-Lung Cellular and Molecular Physiology 283, no. 2 (August 1, 2002): L476—L484. http://dx.doi.org/10.1152/ajplung.00495.2001.

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Heme oxygenases (HOs), essential enzymes for heme metabolism, play an important role in the defense against oxidative stress. In this study, we evaluated the expression and functional significance of HO-1 and HO-2 in the ventilatory muscles of normal rats and rats injected with bacterial lipopolysaccharide (LPS). Both HO-1 and HO-2 proteins were detected inside ventilatory and limb muscle fibers of normal rats. Diaphragmatic HO-1 and HO-2 expressions rose significantly within 1 and 12 h of LPS injection, respectively. Inhibition of the activity of inducible nitric oxide synthase (iNOS) in rats and absence of this isoform in iNOS−/− mice did alter sepsis-induced regulation of muscle HOs. Systemic inhibition of HO activity with chromium mesoporphyrin IX enhanced muscle protein oxidation and hydroxynonenal formation in both normal and septic rats. Moreover, in vitro diaphragmatic force generation declined substantially in response to HO inhibition both in normal and septic rats. We conclude that both HO-1 and HO-2 proteins play an important role in the regulation of muscle contractility and in the defense against sepsis-induced oxidative stress.

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Kim, In Jung, Yannik Brack, Thomas Bayer, and Uwe T. Bornscheuer. "Two novel cyanobacterial α-dioxygenases for the biosynthesis of fatty aldehydes." Applied Microbiology and Biotechnology 106, no. 1 (December 9, 2021): 197–210. http://dx.doi.org/10.1007/s00253-021-11724-x.

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Abstractα-Dioxygenases (α-DOXs) are known as plant enzymes involved in the α-oxidation of fatty acids through which fatty aldehydes, with a high commercial value as flavor and fragrance compounds, are synthesized as products. Currently, little is known about α-DOXs from non-plant organisms. The phylogenic analysis reported here identified a substantial number of α-DOX enzymes across various taxa. Here, we report the functional characterization and Escherichia coli whole-cell application of two novel α-DOXs identified from cyanobacteria: CalDOX from Calothrix parietina and LepDOX from Leptolyngbya sp. The catalytic behavior of the recombinantly expressed CalDOX and LepDOX revealed that they are heme-dependent like plant α-DOXs but exhibit activities toward medium carbon fatty acids ranging from C10 to C14 unlike plant α-DOXs. The in-depth molecular investigation of cyanobacterial α-DOXs and their application in an E. coli whole system employed in this study is useful not only for the understanding of the molecular function of α-DOXs, but also for their industrial utilization in fatty aldehyde biosynthesis.Key points• Two novel α-dioxygenases from Cyanobacteria are reported• Both enzymes prefer medium-chain fatty acids• Both enzymes are useful for fatty aldehyde biosynthesis Graphical abstract

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Empel, Claire, Sripati Jana, and Rene M. Koenigs. "C-H Functionalization via Iron-Catalyzed Carbene-Transfer Reactions." Molecules 25, no. 4 (February 17, 2020): 880. http://dx.doi.org/10.3390/molecules25040880.

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The direct C-H functionalization reaction is one of the most efficient strategies by which to introduce new functional groups into small organic molecules. Over time, iron complexes have emerged as versatile catalysts for carbine-transfer reactions with diazoalkanes under mild and sustainable reaction conditions. In this review, we discuss the advances that have been made using iron catalysts to perform C-H functionalization reactions with diazoalkanes. We give an overview of early examples employing stoichiometric iron carbene complexes and continue with recent advances in the C-H functionalization of C(sp2)-H and C(sp3)-H bonds, concluding with the latest developments in enzymatic C-H functionalization reactions using iron-heme-containing enzymes.

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Clark, RA, and N. Borregaard. "Neutrophils autoinactivate secretory products by myeloperoxidase- catalyzed oxidation." Blood 65, no. 2 (February 1, 1985): 375–81. http://dx.doi.org/10.1182/blood.v65.2.375.375.

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Abstract The neutrophil response to inflammatory stimuli involves the formation of reactive oxygen species and secretion of granule enzymes. In studying secretion of vitamin B12 binding protein by human neutrophils, we noted a major decrease in total recoverable activity from the extracellular fluid plus the stimulated cells (54% of resting cells). Recovery of B12 binding protein from neutrophils exposed to phorbol myristate acetate or opsonized zymosan was significantly enhanced on addition of heme enzyme inhibitors (azide, cyanide) or catalase or when halide-free medium was used. The changes in B12 binding protein recovery were attributable entirely to increases in extracellular fluid levels, and cell pellet content was unaffected. These data indicate extracellular destruction of functional B12 binding protein by the halide-dependent heme enzyme myeloperoxidase and H2O2. Kinetic studies demonstrated rapid secretion of B12 binding protein in the first two to five minutes, followed by its inactivation over the next 20 to 30 minutes. A cell-free extract of vitamin B12 binding protein was readily inactivated on exposure to purified myeloperoxidase, H2O2, and a halide. These findings document a functional interaction among products of the neutrophil specific granules (B12 binding protein), azurophil granules (myeloperoxidase), and metabolic burst (H2O2). They provide an interesting model for the modulation of the inflammatory response by oxidation of secretory products of neutrophils.

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Clark, RA, and N. Borregaard. "Neutrophils autoinactivate secretory products by myeloperoxidase- catalyzed oxidation." Blood 65, no. 2 (February 1, 1985): 375–81. http://dx.doi.org/10.1182/blood.v65.2.375.bloodjournal652375.

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The neutrophil response to inflammatory stimuli involves the formation of reactive oxygen species and secretion of granule enzymes. In studying secretion of vitamin B12 binding protein by human neutrophils, we noted a major decrease in total recoverable activity from the extracellular fluid plus the stimulated cells (54% of resting cells). Recovery of B12 binding protein from neutrophils exposed to phorbol myristate acetate or opsonized zymosan was significantly enhanced on addition of heme enzyme inhibitors (azide, cyanide) or catalase or when halide-free medium was used. The changes in B12 binding protein recovery were attributable entirely to increases in extracellular fluid levels, and cell pellet content was unaffected. These data indicate extracellular destruction of functional B12 binding protein by the halide-dependent heme enzyme myeloperoxidase and H2O2. Kinetic studies demonstrated rapid secretion of B12 binding protein in the first two to five minutes, followed by its inactivation over the next 20 to 30 minutes. A cell-free extract of vitamin B12 binding protein was readily inactivated on exposure to purified myeloperoxidase, H2O2, and a halide. These findings document a functional interaction among products of the neutrophil specific granules (B12 binding protein), azurophil granules (myeloperoxidase), and metabolic burst (H2O2). They provide an interesting model for the modulation of the inflammatory response by oxidation of secretory products of neutrophils.

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Yudenfreund Kravitz, Joslyn, and Vincent L. Pecoraro. "Synthetic and computational modeling of the vanadium-dependent haloperoxidases." Pure and Applied Chemistry 77, no. 9 (January 1, 2005): 1595–605. http://dx.doi.org/10.1351/pac200577091595.

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Vanadium-dependent haloperoxidases that catalyze the halogenation of organic substrates using hydrogen peroxide to oxidize halides are a rare class of enzymes which have an absolute requirement for vanadium. In this article, we describe studies using synthetic, small-molecule analogs of the vanadium(V) active site to functionally mimic the oxidation of bromide and thioethers. In addition, we describe computational studies using density functional theory that help describe the mechanism of catalysis.

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Bruijnincx, Pieter C. A., Gerard van Koten, and Robertus J. M. Klein Gebbink. "Mononuclear non-heme iron enzymes with the 2-His-1-carboxylate facial triad: recent developments in enzymology and modeling studies." Chemical Society Reviews 37, no. 12 (2008): 2716. http://dx.doi.org/10.1039/b707179p.

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Lee, Dongwhan, and Stephen J. Lippard. "Structural and Functional Models of the Dioxygen-Activating Centers of Non-Heme Diiron Enzymes Ribonucleotide Reductase and Soluble Methane Monooxygenase." Journal of the American Chemical Society 120, no. 46 (November 1998): 12153–54. http://dx.doi.org/10.1021/ja9831094.

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Rodrigues, Carolina F., Patrícia T. Borges, Magali F. Scocozza, Diogo Silva, André Taborda, Vânia Brissos, Carlos Frazão, and Lígia O. Martins. "Loops around the Heme Pocket Have a Critical Role in the Function and Stability of BsDyP from Bacillus subtilis." International Journal of Molecular Sciences 22, no. 19 (October 8, 2021): 10862. http://dx.doi.org/10.3390/ijms221910862.

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Bacillus subtilis BsDyP belongs to class I of the dye-decolorizing peroxidase (DyP) family of enzymes and is an interesting biocatalyst due to its high redox potential, broad substrate spectrum and thermostability. This work reports the optimization of BsDyP using directed evolution for improved oxidation of 2,6-dimethoxyphenol, a model lignin-derived phenolic. After three rounds of evolution, one variant was identified displaying 7-fold higher catalytic rates and higher production yields as compared to the wild-type enzyme. The analysis of X-ray structures of the wild type and the evolved variant showed that the heme pocket is delimited by three long conserved loop regions and a small α helix where, incidentally, the mutations were inserted in the course of evolution. One loop in the proximal side of the heme pocket becomes more flexible in the evolved variant and the size of the active site cavity is increased, as well as the width of its mouth, resulting in an enhanced exposure of the heme to solvent. These conformational changes have a positive functional role in facilitating electron transfer from the substrate to the enzyme. However, they concomitantly resulted in decreasing the enzyme’s overall stability by 2 kcal mol−1, indicating a trade-off between functionality and stability. Furthermore, the evolved variant exhibited slightly reduced thermal stability compared to the wild type. The obtained data indicate that understanding the role of loops close to the heme pocket in the catalysis and stability of DyPs is critical for the development of new and more powerful biocatalysts: loops can be modulated for tuning important DyP properties such as activity, specificity and stability.

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Dhar, Manoj Kumar, Sonal Mishra, Archana Bhat, Sudha Chib, and Sanjana Kaul. "Plant carotenoid cleavage oxygenases: structure–function relationships and role in development and metabolism." Briefings in Functional Genomics 19, no. 1 (December 26, 2019): 1–9. http://dx.doi.org/10.1093/bfgp/elz037.

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Abstract A plant communicates within itself and with the outside world by deploying an array of agents that include several attractants by virtue of their color and smell. In this category, the contribution of ‘carotenoids and apocarotenoids’ is very significant. Apocarotenoids, the carotenoid-derived compounds, show wide representation among organisms. Their biosynthesis occurs by oxidative cleavage of carotenoids, a high-value reaction, mediated by carotenoid cleavage oxygenases or carotenoid cleavage dioxygenases (CCDs)—a family of non-heme iron enzymes. Structurally, this protein family displays wide diversity but is limited in its distribution among plants. Functionally, this protein family has been recognized to offer a role in phytohormones, volatiles and signal production. Further, their wide presence and clade-specific functional disparity demands a comprehensive account. This review focuses on the critical assessment of CCDs of higher plants, describing recent progress in their functional aspects and regulatory mechanisms, domain architecture, classification and localization. The work also highlights the relevant discussion for further exploration of this multi-prospective protein family for the betterment of its functional understanding and improvement of crops.

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Journal articles on the topic 'Functional Modeling - Heme Enzymes'

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