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Physiological Sensing of Carbon Dioxide/Bicarbonate/pH via Cyclic Nucleotide Signaling
Jochen Buck,Lonny R. Levin
Sensors , 2011, DOI: 10.3390/s110202112
Abstract: Carbon dioxide (CO2) is produced by living organisms as a byproduct of metabolism. In physiological systems, CO2 is unequivocally linked with bicarbonate (HCO3?) and pH via a ubiquitous family of carbonic anhydrases, and numerous biological processes are dependent upon a mechanism for sensing the level of CO2, HCO3, and/or pH. The discovery that soluble adenylyl cyclase (sAC) is directly regulated by bicarbonate provided a link between CO2/HCO3/pH chemosensing and signaling via the widely used second messenger cyclic AMP. This review summarizes the evidence that bicarbonate-regulated sAC, and additional, subsequently identified bicarbonate-regulate nucleotidyl cyclases, function as evolutionarily conserved CO2/HCO3/pH chemosensors in a wide variety of physiological systems.
Identification of a haem domain in human soluble adenylate cyclase
Sabine Middelhaufe,Martina Leipelt,Lonny?R. Levin,Jochen Buck
Bioscience Reports , 2012, DOI: 10.1042/bsr20120051
Abstract: The second messengers cAMP and cGMP mediate a multitude of physiological processes. In mammals, these cyclic nucleotides are formed by related Class III nucleotidyl cyclases, and both ACs (adenylate cyclases) and GCs (guanylate cyclases) comprise transmembrane receptors as well as soluble isoforms. Whereas sGC (soluble GC) has a well-characterized regulatory HD (haem domain) that acts as a receptor for the activator NO (nitric oxide), very little is known about the regulatory domains of the ubiquitous signalling enzyme sAC (soluble AC). In the present study, we identify a unique type of HD as a regulatory domain in sAC. The sAC-HD (sAC haem domain) forms a larger oligomer and binds, non-covalently, one haem cofactor per monomer. Spectral analyses and mutagenesis reveal a 6-fold co-ordinated haem iron atom, probably with non-typical axial ligands, which can bind both NO and CO (carbon monoxide). Splice variants of sAC comprising this domain are expressed in testis and skeletal muscle, and the HD displays an activating effect on the sAC catalytic core. Our results reveal a novel mechanism for regulation of cAMP signalling and suggest a need for reanalysis of previous studies on mechanisms of haem ligand effects on cyclic nucleotide signalling, particularly in testis and skeletal muscle.
Somatic ‘Soluble’ Adenylyl Cyclase Isoforms Are Unaffected in Sacytm1Lex/Sacytm1Lex ‘Knockout’ Mice
Jeanne Farrell, Lavoisier Ramos, Martin Tresguerres, Margarita Kamenetsky, Lonny R. Levin, Jochen Buck
PLOS ONE , 2008, DOI: 10.1371/journal.pone.0003251
Abstract: Background Mammalian Soluble adenylyl cyclase (sAC, Adcy10, or Sacy) represents a source of the second messenger cAMP distinct from the widely studied, G protein-regulated transmembrane adenylyl cyclases. Genetic deletion of the second through fourth coding exons in Sacytm1Lex/Sacytm1Lex knockout mice results in a male sterile phenotype. The absence of any major somatic phenotype is inconsistent with the variety of somatic functions identified for sAC using pharmacological inhibitors and RNA interference. Principal Findings We now use immunological and molecular biological methods to demonstrate that somatic tissues express a previously unknown isoform of sAC, which utilizes a unique start site, and which ‘escapes’ the design of the Sacytm1Lex knockout allele. Conclusions/Significance These studies reveal increased complexity at the sAC locus, and they suggest that the known isoforms of sAC play a unique function in male germ cells.
Activation of Soluble Adenylyl Cyclase Protects against Secretagogue Stimulated Zymogen Activation in Rat Pancreaic Acinar Cells
Thomas R. Kolodecik, Christine A. Shugrue, Edwin C. Thrower, Lonny R. Levin, Jochen Buck, Fred S. Gorelick
PLOS ONE , 2012, DOI: 10.1371/journal.pone.0041320
Abstract: An early feature of acute pancreatitis is activation of zymogens, such as trypsinogen, within the pancreatic acinar cell. Supraphysiologic concentrations of the hormone cholecystokinin (CCK; 100 nM), or its orthologue cerulein (CER), induce zymogen activation and elevate levels of cAMP in pancreatic acinar cells. The two classes of adenylyl cyclase, trans-membrane (tmAC) and soluble (sAC), are activated by distinct mechanisms, localize to specific subcellular domains, and can produce locally high concentrations of cAMP. We hypothesized that sAC activity might selectively modulate acinar cell zymogen activation. sAC was identified in acinar cells by PCR and immunoblot. It localized to the apical region of the cell under resting conditions and redistributed intracellularly after treatment with supraphysiologic concentrations of cerulein. In cerulein-treated cells, pre-incubation with a trans-membrane adenylyl cyclase inhibitor did not affect zymogen activation or amylase secretion. However, treatment with a sAC inhibitor (KH7), or inhibition of a downstream target of cAMP, protein kinase A (PKA), significantly enhanced secretagogue-stimulated zymogen activation and amylase secretion. Activation of sAC with bicarbonate significantly inhibited secretagogue-stimulated zymogen activation; this response was decreased by inhibition of sAC or PKA. Bicarbonate also enhanced secretagogue-stimulated cAMP accumulation; this effect was inhibited by KH7. Bicarbonate treatment reduced secretagogue-stimulated acinar cell vacuolization, an early marker of pancreatitis. These data suggest that activation of sAC in the pancreatic acinar cell has a protective effect and reduces the pathologic activation of proteases during pancreatitis.
Characterization of Plasmodium falciparum Adenylyl Cyclase-β and Its Role in Erythrocytic Stage Parasites
Eric Salazar, Erin M. Bank, Nicole Ramsey, Kenneth C. Hess, Kirk W. Deitsch, Lonny R. Levin, Jochen Buck
PLOS ONE , 2012, DOI: 10.1371/journal.pone.0039769
Abstract: The most severe form of human malaria is caused by the parasite Plasmodium falciparum. The second messenger cAMP has been shown to be important for the parasite’s ability to infect the host’s liver, but its role during parasite growth inside erythrocytes, the stage responsible for symptomatic malaria, is less clear. The P. falciparum genome encodes two adenylyl cyclases, the enzymes that synthesize cAMP, PfACα and PfACβ. We now show that one of these, PfACβ, plays an important role during the erythrocytic stage of the P. falciparum life cycle. Biochemical characterization of PfACβ revealed a marked pH dependence, and sensitivity to a number of small molecule inhibitors. These inhibitors kill parasites growing inside red blood cells. One particular inhibitor is selective for PfACβ relative to its human ortholog, soluble adenylyl cyclase (sAC); thus, PfACβ represents a potential target for development of safe and effective antimalarial therapeutics.
The Potential of Photo-Talks to Reveal the Development of Scientific Discourses  [PDF]
Cassie Quigley, Gayle Buck
Creative Education (CE) , 2012, DOI: 10.4236/ce.2012.32033
Abstract: This study explores the potential of a photo-elicitation technique, photo-talks (Serriere, 2010), for understanding how young girls understand, employ and translate new scientific discourses. Over the course of a nine week period, 24 kindergarten girls in an urban girls’ academy were observed, videotaped, photographed and interviewed while they were immersed into scientific discourse. This paper explicitly describes how their emerging discursive patterns were made visible through this methodological tool. The findings are presented in vignettes in three themes uncovered during our analysis which are the following: Presented the recollection of the scientific Discourse, Described the understanding of scientific Discourse, and Created an opportunity for the translation into everyday discourse. Science educators can benefit from this methodological tool as a reflective tool with their participants, to validate and/or complicate data. Additionally, this methodological tool serves to make discourse patterns more visible by providing a visual backdrop to the conversations thus revealing the development as it is occurring in young children.
An Adjusted Model for Simple 1,2-Dyotropic Reactions. Ab Initio MO and VB Considerations  [PDF]
Henk M. Buck
Open Journal of Physical Chemistry (OJPC) , 2013, DOI: 10.4236/ojpc.2013.33015

With an adjusted model, we reconsider simple 1,2-dyotropic reactions with the introduction of a concept based on the intramolecular dynamics of a tetrahedron (van ’t Hoff modeling). In fact the dyotropic reactions are strongly related to conversions originated from neighbouring group participation or anchimeric assistance, defined as the interaction of a center with a lone pair of electrons in an atom and the electrons present in aδor π bond. The researchful 1,2-dyotropic reactions, based on the 1,2-interchange of halogens, methyl and hydrogen taking place in a concerted fashion, are in competition with the two-step reaction in which the neighbouring group participation or anchimeric assistance comes to full expression by ionic dissociation of the other exchangeable (halogen) atom. As to be expected there is an essential difference between halogen or methyl exchange regarding the number of electrons participating in the transition state. This aspect becomes evident in the geometries of the corresponding transition state geometries. In this paper we refer to ab initio MO calculations and VB considerations. We consider the 1,2-halogen exchange as a combination of two SN2 reactions each containing four electrons. The van ’t Hoff dynamics appears a useful model in order to illustrate the computations in a straightforward manner.

A conformational B-Z DNA study monitored with phosphatemethylated DNA as a model for epigenetic dynamics focused on 5-(hydroxy)methylcytosine  [PDF]
Henk M. Buck
Journal of Biophysical Chemistry (JBPC) , 2013, DOI: 10.4236/jbpc.2013.42005

This study was directed on the B- into Z-DNA isomerization with alternating CG sequences monitored with artificial DNA model-systems based on methylation of the phosphate backbone. The chemical concept for this transition wherein shielding of the oxygen anions of the backbone phosphates plays an essential role, resulted in the preparation of the phosphatemethylated d(CpG). Even on this primitive level of only two base pair long, the B-Z conformational aspects of this self-complementary duplex could be described in solution with nuclear magnetic resonance (NMR) and circular dichroism (CD) measurements. The exclusivity of this choice became clear after synthesizing phosphatemethylated DNA with longer alternating CG fragments. It could be shown that conflicting conformational effects of the CG and GC fragments resulted in an overall B structure of the phosphatemethylated tetramer d(CPGPCPG). From our model considerations, it is clear that the internal stress introduced by the alternating CG sequences will be promoted by a complete shielding of the phosphate backbone. Elimination of this effect may be realized by a site-specific phosphate shielding. The role of the anti-syn isomerization of G in the CG fragments is clarified by methylation of the phosphate group. This anti-syn transition is absent in corresponding methylphosphonates, suggesting an exclusive role for base-backbone coordination via hydrogen bonding. In addition, we propose that the B- into Z-DNA interconversion may offer a mechanistic view for differences in dynamics between cytosine and its epigenetic derivative 5-methylcytosine. This mechanism has been extended to the demethylation of 5-methylcytosine and the exchange of information between the new epigenetic base, 5-hydroxymethylcytosine and the DNA backbone via an intramolecular phosphorylation. The role of 5-hydroxymethylcytosine in Alzheimer disease has been briefly discussed. In our opinion, this study can be considered as a new dynamic concept for epigenetics based on the dynamics of the B-Z transition in natural and phosphatemethylated DNA.

Three-Center Configuration with Four,Three, and Two Electrons for Carbon,Boron, Hydrogen, and Halogen Exchange. A Model and Theoretical Study with Experimental Evidence  [PDF]
Henk M. Buck
Open Journal of Physical Chemistry (OJPC) , 2014, DOI: 10.4236/ojpc.2014.42006

The introduction of specific sites in organic frames for accommodation of various modes of bonding has been focused on reaction types which are described by using different theoretical models with or without a definite experimental proof. In this study three-center four-, three-, and two-electron systems based on carbon-, boron-, hydrogen-, and halogen exchange are under consideration. Based on the number of electrons in the transition state or transition complex it is shown that all transfer or exchange reactions share the same ratio numbers expressed as the quotient of the transitional bond distance under investigation and its normal bond length. With X-ray data of model systems it was even possible to give the ratio numbers for a three-center four-electron configuration experimental support with additional ab initio data. Furthermore a novel model type of substitution in organic chemistry is introduced through electrophilic insertion, informative for enzyme-substrate interactions based on the lock-and-key model. Reactions based on a three-center two-electron configuration mostly follow a nonlinear transition. In this alignment there will be a pursuit of cyclization for stabilization via homoaromaticity as homocyclopropenyl cation. The molecular dynamics of such a process is discussed based on recent X-ray crystallographic data of the symmetrically bridged, nonclassical geometry of the 2-norbornyl cation. In the present paper the focus is aimed at the transition intermediate of the (classical) 2-norbornyl cation involved in the isomerization into the nonclassical geometry. This model description is compared with a simple molecular rearrangement of the 1-propyl cation into the corner-protonated cyclopropane using the ab initio data. The exclusivity of the former isomerization compared with the latter one could be unambiguously demonstrated by the invention that theintramolecularelectron shift can be expressed in a linear relationship between the concerned electron-donating and accepting bond lengths. Finally, the fluor transitions as divalent atoms in a three-center two-electron configuration are described. The role of fluor in comparison with the other halogens is striking. The attention was focused on an excellent correspondence between the recent chemical and theoretical evidence for a symmetrical fluoronium ionin solution. Simple dialkylfluoroniumions in contrast to the other halonium ions are not present in solution. Although the geometry of the fluoronium ion theoretically can be described as a real minimum,

Interconversion between Planar-Triangle, Trigonal-Pyramid and Tetrahedral Configurations of Boron (B(OH)3 -B(OH)4- ), Carbon (CH3+ -CH3X) and for the Group 15 Elements as Nitrogen (NH3-NH4+ ). A Modelling Description with Ab Initio Results and Pressure-Induced Experimental Evidence  [PDF]
Henk M. Buck
Open Journal of Physical Chemistry (OJPC) , 2015, DOI: 10.4236/ojpc.2015.51001
Abstract: Recently a mechanistic understanding of the pressure-and/or temperature-induced coordination change of boron in a borosilicate glass has been demonstrated by Edwards et al. In situ high-pressure 11B solid-state NMR spectroscopy has been used in combination with ab initio calculations in order to obtain insight in the molecular geometry for the pressure-induced conversion. The results indicate a deformation of the B(OH)3 planar triangle, under isotropic stress, into a trigonal pyramid that serves as a precursor for the formation of a tetrahedral boron configuration. From our point of view, the deformation controlling the out-of-plane transition of boron accompanied with a D3h into C3v geometric change is an interesting transformation because it matches with our molecular description based on Van’t Hoff modelling for the tetrahedral change of carbon in CH3X by substitution of X with nucleophiles via a trigonal bipyramid state in which the transferred carbon is present as a methyl planar triangle “cation”. Van’t Hoff modelling and ab initio calculations have been also applied on the dynamics of the out-of-plane geometry of a transient positively charged carbon in a trigonal pyramidal configuration into a planar trivalent carbon cation. Finally the same model is also used for the C3v trigonal pyramidal configurations as NH3 of the group 15 elements in their nucleophilic abilities.
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