Heme Oxygenase-1/Carbon Monoxide: From Basic Science to Therapeutic Applications

2006 ◽  
Vol 86 (2) ◽  
pp. 583-650 ◽  
Author(s):  
Stefan W. Ryter ◽  
Jawed Alam ◽  
Augustine M. K. Choi
Keyword(s):  
Carbon Monoxide ◽  
Cellular Proliferation ◽  
Biochemical Characterization ◽  
Apoptotic Cell ◽  
Heme Oxygenase 1 ◽  
Bile Pigments ◽  
Cellular Functions ◽  
Rate Limiting Step ◽  
Rate Limiting

The heme oxygenases, which consist of constitutive and inducible isozymes (HO-1, HO-2), catalyze the rate-limiting step in the metabolic conversion of heme to the bile pigments (i.e., biliverdin and bilirubin) and thus constitute a major intracellular source of iron and carbon monoxide (CO). In recent years, endogenously produced CO has been shown to possess intriguing signaling properties affecting numerous critical cellular functions including but not limited to inflammation, cellular proliferation, and apoptotic cell death. The era of gaseous molecules in biomedical research and human diseases initiated with the discovery that the endothelial cell-derived relaxing factor was identical to the gaseous molecule nitric oxide (NO). The discovery that endogenously produced gaseous molecules such as NO and now CO can impart potent physiological and biological effector functions truly represented a paradigm shift and unraveled new avenues of intense investigations. This review covers the molecular and biochemical characterization of HOs, with a discussion on the mechanisms of signal transduction and gene regulation that mediate the induction of HO-1 by environmental stress. Furthermore, the current understanding of the functional significance of HO shall be discussed from the perspective of each of the metabolic by-products, with a special emphasis on CO. Finally, this presentation aspires to lay a foundation for potential future clinical applications of these systems.

Where is the Clinical Breakthrough of Heme Oxygenase-1 / Carbon Monoxide Therapeutics?

2018 ◽  
Vol 24 (20) ◽  
pp. 2264-2282 ◽  
Author(s):  
Christopher P. Hopper ◽  
Lorenz Meinel ◽  
Christoph Steiger ◽  
Leo E. Otterbein
Keyword(s):  
Carbon Monoxide ◽  
Heme Oxygenase ◽  
Capital Investment ◽  
Therapeutic Potential ◽  
Heme Oxygenase 1 ◽  
Commercial Development ◽  
Protective Enzyme ◽  
Rate Limiting Step ◽  
Rate Limiting ◽  
Development Perspective

Heme oxygenase (HO), the rate-limiting step in the degradation of heme to biliverdin, ferrous ion, and carbon monoxide (CO), is an ancestral protective enzyme conserved across phylogenetic domains. While HO was first described in the late 1960s and progressively characterized in the following decades, there has been a surge of innovation over the past twenty years in efforts to leverage the cytoprotective power of HO in a clinical setting. Despite the plethora of preclinical data indicating extraordinary therapeutic potential, HO has remained elusive from the physician’s toolbox. The leading candidate in development, CO, has long been misconstrued as a useless toxic gas. Scientists have crafted an array of CO delivery molecules and devices to harness HO, however, each endeavor was met with limitations preventing translation into clinical practice. In this discussion, we summarize the HO / CO field with a clinical and commercial development perspective. More specifically, given the enormous global efforts and capital investment into the field, we ask: where is the breakthrough therapy?

scholarly journals Characterization of a novel N-acetylneuraminic acid lyase favoring industrial N-acetylneuraminic acid synthesis process

2015 ◽  
Vol 5 (1) ◽  
Author(s):  
Wenyan Ji ◽  
Wujin Sun ◽  
Jinmei Feng ◽  
Tianshun Song ◽  
Dalu Zhang ◽  
...  
Keyword(s):  
Biochemical Characterization ◽  
Acid Synthesis ◽  
Synthesis Process ◽  
Acetylneuraminic Acid ◽  
Cleavage Activity ◽  
Rate Limiting Step ◽  
Synthesis Activity ◽  
Rate Limiting ◽  
Class I Aldolase

Abstract N-Acetylneuraminic acid lyase (NAL, E.C. number 4.1.3.3) is a Class I aldolase that catalyzes the reversible aldol cleavage of N-acetylneuraminic acid (Neu5Ac) from pyruvate and N-acetyl-D-mannosamine (ManNAc). Due to the high Neu5Ac cleavage activity in most isozyme forms, the enzyme catalyzes the rate-limiting step of two biocatalytic reactions producing Neu5Ac in industry. We report the biochemical characterization of a novel NAL from a “GRAS” (General recognized as safe) strain C. glutamicum ATCC 13032 (CgNal). Compared to all previously reported NALs, CgNal exhibited the lowest apparent k cat/Km value for Neu5Ac and highest apparent k cat/Km values for ManNAc and pyruvate, which makes CgNal favor industrial Neu5Ac synthesis process in a non-equilibrium condition. The recombinant CgNal reached the highest expression level (480 mg/L culture) and the highest reported yield of Neu5Ac was achieved (194 g/L, 0.63 M). All these unique properties make CgNal a promising biocatalyst for industrial Neu5Ac biosynthesis. Additionally, although showing the best Neu5Ac synthesis activity among the NAL family, CgNal is more related to dihydrodipicolinate synthase (DHDPS) by phylogenetic analysis. The activities of CgNal towards both NAL's and DHDPS' substrates are fairly high, which indicates CgNal a bi-functional enzyme. The sequence analysis suggests that CgNal might have adopted a unique set of residues for substrates recognition.

Molecular and biochemical characterization of Paragonimus westermani tyrosinase

Parasitology ◽  
2015 ◽  
Vol 142 (6) ◽  
pp. 807-815 ◽  
Author(s):  
Y.-A. BAE ◽  
S.-H. KIM ◽  
C.-S. AHN ◽  
J.-G. KIM ◽  
Y. KONG
Keyword(s):  
Oxidase Activity ◽  
Biochemical Characterization ◽  
Hydroxyl Groups ◽  
Reading Frame ◽  
Paragonimus Westermani ◽  
Rate Limiting Step ◽  
Tanning Process ◽  
Weak Activity ◽  
Rate Limiting

SUMMARYTrematode tyrosinases (TYRs) play a major role in the tanning process during eggshell formation. We investigated the molecular and biochemical features of Paragonimus westermani TYR (PwTYR). The PwTYR cDNA was composed of 1568-bp encompassing a 1422-bp-long open reading frame (474-amino acid polypeptide). A strong phylogenetic relationship with Platyhelminthes and Deuterostomian orthologues was evident. The recombinant PwTYR expressed in prokaryotic cells promptly oxidized diphenol substrates, with a preferential affinity toward ortho-positioned hydroxyl groups. It demonstrated fairly weak activity for monophenol compounds. Diphenol oxidase activity was augmented with an increase of pH from 5·0 to 8·0, while monophenol oxidase activity was highest at an acidic pH and gradually decreased as pH increased. Transcription profile of PwTYR was temporally upregulated along with worm development. PwTYR was specifically localized in vitellocytes and eggs. The results suggested that conversion of tyrosine to L-dihydroxyphenylalanine by PwTYR monophenol oxidase activity might be rate-limiting step during the sclerotization process of P. westermani eggs. The pH-dependent pattern of monophenol and diphenol oxidase activity further proposes that the initial hydroxylation might slowly but steadily progress in acidic secreted vesicles of vitellocytes and the second oxidation process might be rapidly accelerated by neural or weak alkaline pH environments within the ootype.

scholarly journals Biochemical Characterization of the Ran-RanBP1-RanGAP System: Are RanBP Proteins and the Acidic Tail of RanGAP Required for the Ran-RanGAP GTPase Reaction?

2003 ◽  
Vol 23 (22) ◽  
pp. 8124-8136 ◽  
Author(s):  
Michael J. Seewald ◽  
Astrid Kraemer ◽  
Marian Farkasovsky ◽  
Carolin Körner ◽  
Alfred Wittinghofer ◽  
...  
Keyword(s):  
Biochemical Characterization ◽  
Interaction Analysis ◽  
Catalytic Efficiency ◽  
Diffusion Control ◽  
Microtubule Organization ◽  
Rate Limiting Step ◽  
Association Reaction ◽  
Rate Limiting ◽  
Fold Stimulation

ABSTRACT RanBP type proteins have been reported to increase the catalytic efficiency of the RanGAP-mediated GTPase reaction on Ran. Since the structure of the Ran-RanBP1-RanGAP complex showed RanBP1 to be located away from the active site, we reinvestigated the reaction using fluorescence spectroscopy under pre-steady-state conditions. We can show that RanBP1 indeed does not influence the rate-limiting step of the reaction, which is the cleavage of GTP and/or the release of product Pi. It does, however, influence the dynamics of the Ran-RanGAP interaction, its most dramatic effect being the 20-fold stimulation of the already very fast association reaction such that it is under diffusion control (4.5 × 108 M−1 s−1). Having established a valuable kinetic system for the interaction analysis, we also found, in contrast to previous findings, that the highly conserved acidic C-terminal end of RanGAP is not required for the switch-off reaction. Rather, genetic experiments in Saccharomyces cerevisiae demonstrate a profound effect of the acidic tail on microtubule organization during mitosis. We propose that the acidic tail of RanGAP is required for a process during mitosis.

Wavelet Based Structural Analysis of Electroless Deposits in the Diffusion Limited Regime

1994 ◽  
Vol 367 ◽  
Author(s):  
A. Arneodo ◽  
F. Argoul ◽  
A. Kuhn ◽  
J.F. Muzy
Keyword(s):  
Electroless Deposition ◽  
Side Reactions ◽  
Statistical Features ◽  
Diffusion Limited ◽  
Rate Limiting Step ◽  
Limiting Step ◽  
Fractal Patterns ◽  
Rate Limiting ◽  
Comparative Structural Characterization

AbstractWe discuss the actual relevance of thin gap geometry electrodeposition to generate fractal patterns that mimic the morphology of Witten and Sander's diffusion-limited aggregates (DLA). Eliminating migration and convection, as well as electrochemical side reactions, we show that electroless deposition is a good candidate to meet the requirements for diffusion to be the rate limiting step of the growth process. We use the wavelet transform microscope to achieve a comparative structural characterization of both experimental electroless deposits and numerical DLA clusters. The fact that five-fold symmetry and Fibonacci hierarchical ordering are found as common predominant statistical features is, to our knowledge, the first demonstration, relying on an appropriate structural fractal analysis, of the existence of DLA morphologies in an experimental context.

An internal enhancer regulates heme- and cadmium-mediated induction of human heme oxygenase-1

2003 ◽  
Vol 285 (3) ◽  
pp. F515-F523 ◽  
Author(s):  
Nathalie Hill-Kapturczak ◽  
Eric Sikorski ◽  
Christy Voakes ◽  
Jairo Garcia ◽  
Harry S. Nick ◽  
...  
Keyword(s):  
Heme Oxygenase ◽  
Tissue Injury ◽  
Molecular Regulation ◽  
Heme Oxygenase 1 ◽  
Aortic Endothelial Cells ◽  
Rate Limiting Step ◽  
Limiting Step ◽  
Beneficial Response ◽  
Enhancer Function ◽  
Rate Limiting

Heme oxygenase-1 (HO-1) catalyzes the rate-limiting step in heme degradation, releasing iron, carbon monoxide, and biliverdin. Induction of HO-1 is an adaptive and beneficial response in renal and nonrenal settings of tissue injury. The purpose of this study was to characterize the regulation of the human HO-1 gene in renal proximal tubule and aortic endothelial cells in response to heme and cadmium. Evaluation of multiple human HO-1 promoter-reporter constructs up to -9.1 kb demonstrated only a partial response to heme and cadmium. In an effort to mimic endogenous stimulus-dependent levels of HO-1 induction, we evaluated the entire 12.5 kb of the human HO-1 gene, including introns and exons, in conjunction with a -4.5-kb human HO-1 promoter and observed significant heme- and cadmium-mediated induction of the reporter gene, suggesting the presence of an internal enhancer. Enhancer function was orientation independent and required a region between -3.5 and -4.5 kb of the human HO-1 promoter. Our studies identified a novel enhancer internal to the human HO-1 gene that, in conjunction with the HO-1 promoter, recapitulates heme- and cadmium-mediated induction of the endogenous HO-1 gene. Elucidation of the molecular regulation of the human HO-1 gene will allow for the development of therapeutic strategies to manipulate HO-1 gene expression in pathological states.

Vapor Transport Deposition and Characterization of Polycrystalline CdTe Solar Absorbers

2003 ◽  
Vol 763 ◽  
Author(s):  
James M. Kestner ◽  
Sarah McElvain ◽  
Colin A. Wolden ◽  
Stephen Kelly ◽  
Tim R. Ohno ◽  
...  
Keyword(s):  
Vapor Transport ◽  
Buffer Layers ◽  
High Rate ◽  
X Ray Diffraction ◽  
Solar Absorbers ◽  
Rate Limiting Step ◽  
Rate Limiting ◽  
Substrate Temperatures ◽  
Vapor Transport Deposition

AbstractVapor transport deposition is being developed for high-rate synthesis of CdTe thin films. Films have been deposited at rates in excess of 20 μm/min. Thegrowth ratedependenceon source temperature yielded an apparent activation energy of 42 kcal/mol, in good agreement with the theoretical value for CdTe sublimation (45.7 kcal/mol). For substrate temperatures greater than 400°C the rate limiting step was resublimation. This phenomenon had a dramatic influence on morphology, although x-ray diffraction of all films indicated a strong (111) orientation. A preliminary device optimization investigating the effect of CdTe deposition temperature, post-deposition CdCl2 anneal parameters, alternative back contacts, and high-resistance buffer layers yielded a best cell with efficiency of 9.8% (704 mV Voc, 21.0mA/cm2 Jsc, 66% FF).

scholarly journals Imaging specific cellular glycan structures using glycosyltransferases via click chemistry

2017 ◽  
Author(s):  
Zhengliang L Wu ◽  
Anthony Person ◽  
Matthew Anderson ◽  
Barbara Burroughs ◽  
Timothy Tatge ◽  
...  
Keyword(s):  
Umbilical Vein ◽  
Functional Characterization ◽  
Tn Antigen ◽  
Stem Cell Line ◽  
Rate Limiting Step ◽  
Architectural Features ◽  
Huvec Cells ◽  
Umbilical Vein Endothelial Cells ◽  
Rate Limiting

AbstractHeparan sulfate (HS) is a polysaccharide fundamentally important for biologically activities. T/Tn antigens are universal carbohydrate cancer markers. Here, we report the specific imaging of these carbohydrates using a mesenchymal stem cell line and human umbilical vein endothelial cells (HUVEC). The staining specificities were demonstrated by comparing imaging of different glycans and validated by either removal of target glycans, which results in loss of signal, or installation of target glycans, which results in gain of signal. As controls, representative key glycans including O-GlcNAc, lactosaminyl glycans and hyaluronan were also imaged. HS staining revealed novel architectural features of the extracellular matrix (ECM) of HUVEC cells. Results from T/Tn antigen staining suggest that O-GalNAcylation is a rate-limiting step for O-glycan synthesis. Overall, these highly specific approaches for HS and T/Tn antigen imaging should greatly facilitate the detection and functional characterization of these biologically important glycans.

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