Thursday, July 28, 2016

Pharmacological Chaperones that Protect Tetrahydrobiopterin Dependent Aromatic Amino Acid Hydroxylases Through Different Mechanisms

Author(s):

Magnus Hole, Ana Jorge-Finnigan, Jarl Underhaug, Knut Teigen and Aurora MartinezPages 1-12 (12)

Abstract:


The aromatic amino acid hydroxylase (AAAH) enzyme family includes phenylalanine hydroxylase (PAH), tyrosine hydroxylase (TH) and the tryptophan hydroxylases (TPH1 and TPH2). All four members of the AAAH family require iron, dioxygen and the cofactor (6R)-L-erythro-5,6,7,8-tetrahydrobiopterin (BH4) to hydroxylate their respective substrates. The AAAHs are involved in severe diseases; whereas polymorphisms and variants in the TPH genes are associated to neuropsychiatric disorders, mutations in PAH and TH are responsible for the autosomal recessive disorders phenylketonuria (PKU) and TH deficiency (THD), respectively. A large number of PKU and THD-causing mutations give rise to unstable, misfolded proteins. The degree of conformational instability correlates well with the severity of the patient phenotypes, underlying the relevance of searching for stabilizing compounds that may protect from loss of protein and activity in vivo. Supplementation with the cofactor BH4 exerts a multifactorial response in PAH, where one of the main mechanisms for the induced increase in PAH activity in BH4-responsive PKU patients appears to be a pharmacological chaperone effect. For TH the stabilizing effect of BH4 is less established. On the other hand, a number of compounds with pharmacological chaperone potential for PKU and THD mutants have been discovered. The stabilizing effect of these compounds has been established in vitro, in cells and in animal models. A recent study with TH has revealed different mechanisms for the action of pharmacological chaperones and identifies a subtype of compounds that preserve TH activity by weak binding to the catalytic iron. It is expected that synergistic combinations of different pharmacological chaperones could provide patient-tailored therapeutic options.

Keywords:

Mutation, protein stability, misfolding correction, pharmacological chaperones, phenylketonuria, tyrosine hydroxylase deficiency

Affiliation:

Department of Biomedicine and K.G. Jebsen Center for Research on Neuropsychiatric Disorders, University of Bergen, Bergen Norway


Read Full-Text article

Insights into a Critical Role of the FOXO3a-FOXM1 Axis in DNA Damage Response and Genotoxic Drug Resistance

Author(s):

Gabriela Nestal de Moraes, Laura Bella, Stefania Zona, Matthew J. Burton and Eric W.-F. LamPages 164-177 (14)

Abstract:


FOXO3a and FOXM1 are two forkhead transcription factors with antagonistic roles in cancer and DNA damage response. FOXO3a functions like a typical tumour suppressor, whereas FOXM1 is a potent oncogene aberrantly overexpressed in genotoxic resistant cancers. FOXO3a not only represses FOXM1 expression but also its transcriptional output. Recent research has provided novel insights into a central role for FOXO3a and FOXM1 in DNA damage response. The FOXO3a-FOXM1 axis plays a pivotal role in DNA damage repair and the accompanied cellular response through regulating the expression of genes essential for DNA damage sensing, mediating, signalling and repair as well as for senescence, cell cycle and cell death control. In this manner, the FOXO3a-FOXM1 axis also holds the key to cell fate decision in response to genotoxic therapeutic agents and controls the equilibrium between DNA repair and cell termination by cell death or senescence. As a consequence, inhibition of FOXM1 or reactivation of FOXO3a in cancer cells could enhance the efficacy of DNA damaging cancer therapies by decreasing the rate of DNA repair and cell survival while increasing senescence and cell death. Conceptually, targeting FOXO3a and FOXM1 may represent a promising molecular therapeutic option for improving the efficacy and selectivity of DNA damage agents, particularly in genotoxic agent resistant cancer. In addition, FOXO3a, FOXM1 and their downstream transcriptional targets may also be reliable diagnostic biomarkers for predicting outcome, for selecting therapeutic options, and for monitoring treatments in DNA-damaging agent therapy.

Keywords:

Cancer, DNA damage, drug resistance, FOXM1, FOXO3a, genotoxic agents, transcriptional targets.

Affiliation:

Department of Surgery and Cancer, Imperial College London, Hammersmith Hospital Campus, Du Cane Road, London, W12 0NN, UK.

Graphical Abstract:



Read Full-Text article

Targeted Thromboelastographic (TEG) Blood Component and Pharmacologic Hemostatic Therapy in Traumatic and Acquired Coagulopathy

Author(s):

Mark Walsh, Stephanie Fritz, Daniel Hake, Michael Son, Sarah Greve, Manar Jbara, Swetha Chitta, Braxton Fritz, Adam Miller, Mary K Bader, Jonathon McCollester, Sophia Binz, Alyson Liew-Spilger, Scott Thomas, Anton Crepinsek, Faisal Shariff, Victoria Ploplis and Francis J. CastellinoPages 954-970 (17)

Abstract:


Trauma-induced coagulopathy (TIC) is a recently described condition which traditionally has been diagnosed by the common coagulation tests (CCTs) such as prothrombin time/international normalized ratio (PT/INR), activated partial thromboplastin time (aPTT), platelet count, and fibrinogen levels. The varying sensitivity and specificity of these CCTs have led trauma coagulation researchers and clinicians to use Viscoelastic Tests (VET) such as Thromboelastography (TEG) to provide Targeted Thromboelastographic Hemostatic and Adjunctive Therapy (TTHAT) in a goal directed fashion to those trauma patients in need of hemostatic resuscitation. This review describes the utility of VETs, in particular, TEG, to provide TTHAT in trauma and acquired non-trauma-induced coagulopathy.

Keywords:

Thromboelastography, point-of-care, acquired coagulopathy, blood component therapy, systemic hemostatic agents, trauma-induced coagulopathy, hemostatic resuscitation, tranexamic acid, targeted pharmacologic therapy.

Affiliation:

Memorial Hospital of South Bend, South Bend, Indiana 46601, USA.

Graphical Abstract:



Read Full-Text article

Structural and Functional Aspects of Class A Carbapenemases

Author(s):

Thierry Naas, Laurent Dortet and Bogdan I. IorgaPages 1006-1028 (23)

Abstract:


The fight against infectious diseases is probably one of the greatest public health challenges faced by our society, especially with the emergence of carbapenem-resistant gram-negatives that are in some cases pan-drug resistant. Currently, β-lactamase-mediated resistance does not spare even the newest and most powerful β-lactams (carbapenems), whose activity is challenged by carbapenemases. The worldwide dissemination of carbapenemases in gram-negative organisms threatens to take medicine back into the pre-antibiotic era since the mortality associated with infections caused by these “superbugs” is very high, due to limited treatment options. Clinically-relevant carbapenemases belong either to metallo- β- lactamases (MBLs) of Ambler class B or to serine-β -lactamases (SBLs) of Ambler class A and D enzymes. Class A carbapenemases may be chromosomally-encoded (SME, NmcA, SFC-1, BIC-1, PenA, FPH-1, SHV-38), plasmid-encoded (KPC, GES, FRI-1) or both (IMI). The plasmid-encoded enzymes are often associated with mobile elements responsible for their mobilization. These enzymes, even though weakly related in terms of sequence identities, share structural features and a common mechanism of action. They variably hydrolyse penicillins, cephalosporins, monobactams, carbapenems, and are inhibited by clavulanate and tazobactam. Three-dimensional structures of class A carbapenemases, in the apo form or in complex with substrates/inhibitors, together with site-directed mutagenesis studies, provide essential input for identifying the structural factors and subtle conformational changes that influence the hydrolytic profile and inhibition of these enzymes. Overall, these data represent the building blocks for understanding the structure-function relationships that define the phenotypes of class A carbapenemases and can guide the design of new molecules of therapeutic interest.

Keywords:

Biochemical properties, carbapenemase, class A, crystallography, molecular modeling, mutagenesis.

Affiliation:

Service de Bactériologie- Hygiène, Hôpital de Bicêtre, APHP, EA7361, Faculté de Médecine Paris- Sud, LabEx LERMIT, Le Kremlin-Bicêtre, France.

Graphical Abstract:



Read Full-Text article