Structure—Function Relationships of EcDOS, a Heme‐Regulated Phosphodiesterase from Escherichia coli

Sasakura, Yukie; Yoshimura-Suzuki, Tokiko; Kurokawa, H.; Shimizu, Tôru

doi:10.1002/chin.200619265

Cited by 25 publications

(58 citation statements)

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“…Arg-97 H-bonds to heme-bound O 2 , stabilizing the oxyferrous form by lowering its autoxidation rate (99). E. coli Dos was also suggested to be a redox sensor because the ferric state (readily formed in vitro with H 2 O replacing the Met-95 ligand) has diminished PDE activity with cAMP (98). However, the reduced cytoplasm of E. coli and stabilizing Arg-97/O 2 interactions probably maintain the oxyferrous form in vivo.…”

Section: Other Gas Sensorsmentioning

confidence: 99%

Heme Sensor Proteins

Girvan

Munro

2013

Journal of Biological Chemistry

128

116

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Heme is a prosthetic group best known for roles in oxygen transport, oxidative catalysis, and respiratory electron transport. Recent years have seen the roles of heme extended to sensors of gases such as O 2 and NO and cell redox state, and as mediators of cellular responses to changes in intracellular levels of these gases. The importance of heme is further evident from identification of proteins that bind heme reversibly, using it as a signal, e.g. to regulate gene expression in circadian rhythm pathways and control heme synthesis itself. In this minireview, we explore the current knowledge of the diverse roles of heme sensor proteins. Heme-responsive Proteins: Defining FeaturesHeme homeostasis is crucial. Free heme at Ͼ1 M is cytotoxic, mainly by producing reactive oxygen species. Iron intake accounts for only a small proportion of mammalian requirements, so iron recycling (particularly from heme) is critical (1). Tight regulation of heme synthesis/breakdown is needed. Heme regulates its own fate and controls several other biological processes. Heme-responsive proteins elicit cellular responses by binding/debinding heme or via changes in heme ligation (e.g. by gases) or redox state. They can be divided into two classes: nuclear receptor (NR) 2 hemoproteins and heme sensors with no NR function. Each heme-responsive protein has a heme regulatory motif (HRM), usually containing a CP motif (2). The Cys residue of the CP motif is an axial heme ligand. No other residues are conserved across the protein class. The wider relevance of the CP motif is unclear because other hemoproteins (e.g. prostaglandin E 2 synthase, chloroperoxidase, and some cytochromes P450) also have a CP motif. The properties of members of the two main classes are described below. NR HemoproteinsSeveral heme-binding proteins occur in the NR superfamily, which is the largest transcription factor superfamily (summarized in Table 1). NRs bind specific DNA motifs in response to small molecule signaling. They generally share conserved domain architecture, with a DNA-binding region containing two zinc fingers, a ligand-binding domain, and activation domains (3). Usually, ligand binding induces conformational changes that dissociate partner proteins, allowing DNA binding and/or changes to dimerization status or cellular localization that enable the protein to elicit a response. A subfamily of NRs binds heme at their ligand-binding domain and so act as heme sensors, as discussed below. Circadian Rhythm Heme SensorsCircadian rhythms are regulated by feedback loops at transcriptional/translational levels. Heme is critical in this process (4). In vertebrates, the expression of several day/night cycle genes, as well as Rev-erb␣, is controlled by binding a heterodimer of Clock (or NPAS2 (neuronal PAS domain protein 2)) and Bmal1 to their 5Ј-UTR, thus switching on transcription. Expression of Bmal1 and NPAS2/Clock is repressed in turn by binding of Rev-erb␣ to a homodimeric partner (5). Rev-erb␣ and homologs (Rev-erb␤ and E75, with the latter involved in inse...

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Section: Other Gas Sensorsmentioning

confidence: 99%

Heme Sensor Proteins

Girvan

Munro

2013

Journal of Biological Chemistry

128

116

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“…In general, the heme-based oxygen sensors are composed of an N-terminal heme-bound oxygen-sensing/binding domain containing globin, PAS (Per-Arnt-Sim), or GAF (cGMP-specific and cGMP-stimulated phosphodiesterases, adenylate cyclases, and Escherichia coli FhlA) folds and a C-terminal functional/catalytic domain ( Fig. 1) (7)(8)(9)(10)(11)(12)(13). O 2 (the first signal) binds to/dissociates from the heme iron complex and induces a structural change (the second signal) in the heme-bound oxygen-sensing domain of the protein.…”

Section: What Is a Heme-based Oxygen Sensor?mentioning

confidence: 99%

Heme-based Globin-coupled Oxygen Sensors: Linking Oxygen Binding to Functional Regulation of Diguanylate Cyclase, Histidine Kinase, and Methyl-accepting Chemotaxis

Martínková

Kitanishi

Shimizu

2013

Journal of Biological Chemistry

Self Cite

107

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An emerging class of novel heme-based oxygen sensors containing a globin fold binds and senses environmental O 2 via a heme iron complex. Structure-function relationships of oxygen sensors containing a heme-bound globin fold are different from those containing heme-bound PAS and GAF folds. It is thus worth reconsidering from an evolutionary perspective how heme-bound proteins with a globin fold similar to that of hemoglobin and myoglobin could act as O 2 sensors. Here, we summarize the molecular mechanisms of heme-based oxygen sensors containing a globin fold in an effort to shed light on the O 2 -sensing properties and O 2 -stimulated catalytic enhancement observed for these proteins.

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“…However, there are examples in the literature of enzymes that are considered to have an important function despite similarly poor kinetic constants. For example, the heme-regulated phosphodiesterase has a rate constant of 0.15 min 21 with cAMP and a dissociation constant of 0.3 mM for nitric oxide [27].…”

Section: Perspectivesmentioning

confidence: 99%

Aryl acylamidase activity of human serum albumin witho-nitrotrifluoroacetanilide as the substrate

Masson

Froment

Darvesh

et al. 2007

Journal of Enzyme Inhibition and Medicinal Chemistry

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Albumin is generally regarded as an inert protein with no enzyme activity. However, albumin has esterase activity as well as aryl acylamidase activity. A new acetanilide substrate, o-nitrotrifluoroacetanilide (o-NTFNAC), which is more reactive than the classical o-nitroacetanilide, made it possible to determine the catalytic parameters for hydrolysis by fatty-acid free human serum albumin. Owing to the low enzymatic activity of albumin, kinetic studies were performed at high albumin concentration (0.075 mM). The albumin behavior with this substrate was Michaelis-Menten like. Kinetic analysis was performed according to the formalism used for catalysis at high enzyme concentration. This approach provided values for the turnover and dissociation constant of the albumin-substrate complex: k cat ¼ 0.13^0.02 min2 1 and K s ¼ 0.67^0.04 mM. MALDI-TOF experiments showed that unlike the ester substrate p-nitrophenyl acetate, o-NTFNAC does not form a stable adduct (acetylated enzyme). Kinetic analysis and MALDI-TOF experiments demonstrated that hydrolysis of o-NTFNAC by albumin is fully rate-limited by the acylation step (k cat ¼ k 2 ). Though the aryl acylamidase activity of albumin is low (k cat /K s ¼ 195 M 21 min 21 ), because of its high concentration in human plasma (0.6 -1 mM), albumin may participate in hydrolysis of aryl acylamides through second-order kinetics. This suggests that albumin may have a role in the metabolism of endogenous and exogenous aromatic amides, including drugs and xenobiotics.

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Structure—Function Relationships of EcDOS, a Heme‐Regulated Phosphodiesterase from Escherichia coli

Cited by 25 publications

References 1 publication

Heme Sensor Proteins

Heme Sensor Proteins

Heme-based Globin-coupled Oxygen Sensors: Linking Oxygen Binding to Functional Regulation of Diguanylate Cyclase, Histidine Kinase, and Methyl-accepting Chemotaxis

Aryl acylamidase activity of human serum albumin witho-nitrotrifluoroacetanilide as the substrate

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