Dopa-responsive dystonia (DRD) and DRD plus are diseases of the dopamine pathway with sizeable genetic diversity and myriad presentations. DRD has onset in childhood or adolescence with focal dystonia, commonly affecting lower limb, diurnal fluctuations with evening worsening of symptoms and a demonstrable sleep benefit. DRD \"plus\" has \"atypical features\" which include infantile onset, psychomotor delay, cognitive abnormalities, oculogyric crisis, seizures, irritability, spasticity, hypotonia, ptosis, hyperthermia and cerebellar dysfunction. Neurodegeneration, however, is not a feature of either DRD or DRD-plus disorders. Tetrahydrobiopterin (BH4), a key cofactor, deficiency leads to inadequate dopamine and serotonin synthesis. Norepinephrine deficiency may coexist, depending on the enzyme defect. Hyperphenylalaninemia (HPA) is a clue for BH4 paucity. However, HPA is conspicuously absent in autosomal-dominant guanosine triphosphate cyclohydrolase 1 deficiency and sepiapterin reductase deficiency. DRD look-alike is a group of neurodegenerative disorders involving the nigrostriatal dopaminergic system, which could present with dystonia responsive to dopaminergic drugs or neurodegenerative or non-neurodegenerative disorders without involving the nigrostriatal dopaminergic system yet responsive to levodopa. Although levodopa is the mainstay of therapy, response to this drug can be unsatisfactory in DRD plus and DRD look-alike and other drugs are tried. Simultaneous management of HPA leads to remarkable improvement in both motor and cognitive functions. The aim of this review is to help neurology practitioners in treating patients with DRD, DRD-plus and DRD look-alike as many of them have excellent outcome with appropriate therapy.

Dynamin superfamily proteins are multidomain mechano-chemical GTPases which are implicated in nucleotide-dependent membrane remodeling events. A prominent feature of these proteins is their assembly- stimulated mechanism of GTP hydrolysis. The molecular basis for this reaction has been initially clarified for the dynamin-related guanylate binding protein 1 (GBP1) and involves the transient dimerization of the GTPase domains in a parallel head-to-head fashion. A catalytic arginine finger from the phosphate binding (P-) loop is repositioned toward the nucleotide of the same molecule to stabilize the transition state of GTP hydrolysis. Dynamin uses a related dimerization-dependent mechanism, but instead of the catalytic arginine, a monovalent cation is involved in catalysis. Still another variation of the GTP hydrolysis mechanism has been revealed for the dynamin-like Irga6 which bears a glycine at the corresponding position in the P-loop. Here, we highlight conserved and divergent features of GTP hydrolysis in dynamin superfamily proteins and show how nucleotide binding and hydrolysis are converted into mechano-chemical movements. We also describe models how the energy of GTP hydrolysis can be harnessed for diverse membrane remodeling events, such as membrane fission or fusion. © 2016 Wiley Periodicals, Inc. Biopolymers 105: 580-593, 2016.

This review addresses the regulatory consequences of the binding of GTP to the alpha subunits (Gα) of heterotrimeric G proteins, the reaction mechanism of GTP hydrolysis catalyzed by Gα and the means by which GTPase activating proteins (GAPs) stimulate the GTPase activity of Gα. The high energy of GTP binding is used to restrain and stabilize the conformation of the Gα switch segments, particularly switch II, to afford stable complementary to the surfaces of Gα effectors, while excluding interaction with Gβγ, the regulatory binding partner of GDP-bound Gα. Upon GTP hydrolysis, the energy of these conformational restraints is dissipated and the two switch segments, particularly switch II, become flexible and are able to adopt a conformation suitable for tight binding to Gβγ. Catalytic site pre-organization presents a significant activation energy barrier to Gα GTPase activity. The glutamine residue near the N-terminus of switch II (Glncat ) must adopt a conformation in which it orients and stabilizes the γ phosphate and the water nucleophile for an in-line attack. The transition state is probably loose with dissociative character; phosphoryl transfer may be concerted. The catalytic arginine in switch I (Argcat ), together with amide hydrogen bonds from the phosphate binding loop, stabilize charge at the β-γ bridge oxygen of the leaving group. GAPs that harbor \"regulator of protein signaling\" (RGS) domains, or structurally unrelated domains within G protein effectors that function as GAPs, accelerate catalysis by stabilizing the pre-transition state for Gα-catalyzed GTP hydrolysis, primarily by restraining Argcat and Glncat to their catalytic conformations. © 2016 Wiley Periodicals, Inc. Biopolymers 105: 449-462, 2016.

Widespread utilization of small GTPases as major regulatory hubs in many different biological systems derives from a conserved conformational switch mechanism that facilitates cycling between GTP-bound active and GDP-bound inactive states under control of guanine nucleotide exchange factors (GEFs) and GTPase activating proteins (GAPs), which accelerate slow intrinsic rates of activation by nucleotide exchange and deactivation by GTP hydrolysis, respectively. Here we review developments leading to current understanding of intrinsic and GAP catalyzed GTP hydrolytic reactions in small GTPases from structural, molecular and chemical mechanistic perspectives. Despite the apparent simplicity of the GTPase cycle, the structural bases underlying the hallmark hydrolytic reaction and catalytic acceleration by GAPs are considerably more diverse than originally anticipated. Even the most fundamental aspects of the reaction mechanism have been challenging to decipher. Through a combination of experimental and in silico approaches, the outlines of a consensus view have begun to emerge for the best studied paradigms. Nevertheless, recent observations indicate that there is still much to be learned. © 2016 Wiley Periodicals, Inc. Biopolymers 105: 431-448, 2016.

Translational GTPases (trGTPases) play key roles in facilitating protein synthesis on the ribosome. Despite the high degree of evolutionary conservation in the sequences of their GTP-binding domains, the rates of GTP hydrolysis and nucleotide exchange vary broadly between different trGTPases. EF-Tu, one of the best-characterized model G proteins, evolved an exceptionally rapid and tightly regulated GTPase activity, which ensures rapid and accurate incorporation of amino acids into the nascent chain. Other trGTPases instead use the energy of GTP hydrolysis to promote movement or to ensure the forward commitment of translation reactions. Recent data suggest the GTPase mechanism of EF-Tu and provide an insight in the catalysis of GTP hydrolysis by its unusual activator, the ribosome. Here we summarize these advances in understanding the functional cycle and the regulation of trGTPases, stimulated by the elucidation of their structures on the ribosome and the progress in dissecting the reaction mechanism of GTPases. © 2016 Wiley Periodicals, Inc. Biopolymers 105: 463-475, 2016.

Platelet is activated through signal transduction, that mainly includes phospholipase-beta (PLCbeta) pathway, protein tyrosine kinases (PTK) pathway, phosphatidylinositol3-kinase (PI3-K) pathway, mitogen-activated protein kinases (MAPK) pathway, cyclic adenosine monophosphate-protein kinase A (cAMP-PKA) pathway and phospholipase A2 (PLA2) pathway. This article focuses on the relationship between signal transduction and platelet activation.

BACKGROUND: T-cell lymphoid blastic phase (BP) transformation is rare in chronic myelogenous leukemia (CML). 2-amino-9-beta-D-arabinosyl-6-methoxy-9H-guanine (GW506U78), a prodrug of arabinosylguanine (ara-G), is effective in T-cell leukemias.
METHODS: The authors present a case of a 48-year-old male with Philadelphia chromosome (Ph) positive CML and T-cell lymphoid BP after 17 months in the chronic phase.
RESULTS: Plasma pharmacokinetic studies after an infusion of GW506U78 at a dose of 40 mg/kg showed GW506U78 concentrations of 60 microM, and a peak ara-G concentration of 260 microM in the plasma. Cellular ara-G triphosphate (ara-GTP) concentration in the peripheral blood T-lymphoblasts was 80 microM at the end of GW506U78 infusion and reached a maximum of 150 microM. The patient achieved a complete response that lasted 13 months. Severe neurotoxicity related to GW506U78 was observed.
CONCLUSIONS: GW506U78 showed antileukemic activity against Ph positive T-cell BP CML. Neurotoxicity was dose-limiting in this patient. Treatment with GW506U78 and modulation of ara-GTP concentrations are therapeutic strategies that require further exploration in T-cell malignancies. Investigation of other dosing schedules may limit neurotoxicity.

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Both actin and tubulin, the major proteins of the cytoskeleton, bind nucleotide triphosphate (NTP) and exhibit the phenomenon of \"polymerization-coupled\" NTP hydrolysis. In this report I review the nature of polymerization-coupled NTP hydrolysis, and its possible role in the cellular function of actin and tubulin. Polymerization-coupled hydrolysis may be viewed as simply reflecting differences in the NTPase activity of free subunit as compared to polymer. Making assumptions concerning the values of various rate constants, it is possible to write expressions for the effects of NTP hydrolysis on the kinetics of polymerization. The role of NTP hydrolysis may be viewed in at least three different ways: 1) Hydrolysis alters the kinetics of assembly and disassembly. This leads to a consideration of the role of subunit flow in microtubule and microfilament function. 2) Hydrolysis is an essentially irreversible step that separates the assembly and disassembly reactions. This suggests a role of NTP in the regulation of polymer content during cellular cycles of assembly and disassembly. 3) NTP may allow transient stabilization of intersubunit bonds. This suggests a role of NTP in nucleation and possible regulation of nonequilibrium states of assembly.

GTP hydrolysis associated with polymerization is a distinctive feature of microtubule assembly. This reaction may be fundamentally linked to the dynamic properties of microtubules in vivo. Kinetic analysis of the connection between microtubule assembly and associated GTP hydrolysis indicates that these two events are kinetically uncoupled, GTP hydrolysis occurring after tubulin incorporation in the microtubule. As a consequence, the combination of the diffusional incorporation of GTP in microtubules at steady-state and of subsequent GTP hydrolysis results in the formation of a steady-state GTP cap at microtubule ends. The interplay between GTP and GDP at microtubule ends is examined. Inhibition by GDP of steady-state GTP hydrolysis at microtubule ends and of microtubule elongation is understood within a tight reversible binding of GDP at microtubule ends generating \'inactive\' elongation sites. Nucleotides are freely exchangeable at microtubule ends. This result indicates that the nature of the nucleotide present at microtubule ends must be considered in a model for microtubule assembly. These data are pooled in order to define the general features of a model describing microtubule assembly and treadmilling in terms somewhat different from previously proposed models.