Implications of Pyran Cyclization and Pterin Conformation on Oxidized Forms of the Molybdenum Cofactor.

The large family of mononuclear molybdenum and tungsten enzymes all possess the special ligand molybdopterin (MPT), which consists of a metal-binding dithiolene chelate covalently bound to a pyranopterin group. MPT pyran cyclization/scission processes have been proposed to modulate the reactivity of the metal center during catalysis. We have designed several small-molecule models for the Mo-MPT cofactor that allow detailed investigation into how pyran cyclization modulates electronic communication between the dithiolene and pterin moieties and how this cyclization alters the electronic environment of the molybdenum catalytic site. Using a combination of cyclic voltammetry, vibrational spectroscopy (FT-IR and rR), electronic absorption spectroscopy, and X-ray absorption spectroscopy, distinct changes in the Mo≡O stretching frequency, Mo(V/IV) reduction potential, and electronic structure across the pterin-dithiolene ligand are observed as a function of pyran ring closure. The results are significant, for they reveal that a dihydropyranopterin is electronically coupled into the Mo-dithiolene group due to a coplanar conformation of the pterin and dithiolene units, providing a mechanism for the electron-deficient pterin to modulate the Mo environment. A spectroscopic signature identified for the dihydropyranopterin-dithiolene ligand on Mo is a strong dithiolene → pterin charge transfer transition. In the absence of a pyran group bridge between pterin and dithiolene, the pterin rotates out of plane, largely decoupling the system. The results support a hypothesis that pyran cyclization/scission processes in MPT may function as a molecular switch to electronically couple and decouple the pterin and dithiolene to adjust the redox properties in certain pyranopterin molybdenum enzymes.

The location of pain and urgency sensations during cystometry.

AIMS: The relationship between bladder pain and urinary urgency sensations is poorly understood. We analyzed the relationship between locations and intensities of urgency and pain sensations felt during filling cystometry. METHODS: Participants completed the King's Health Questionnaire (KHQ) to indicate presence of bladder pain or urgency. During cystometry, participants scored the intensity of urgency and pain, both in the suprapubic and the urethral region, on a VAS scale of 0-10 at a baseline, at first desire, normal desire, strong desire to void, and at maximum cystometric capacity during filling. We allocated the participants to six groups; those reporting urgency or not, pain or not, both symptoms and neither. Friedman's Test was used to ascertain if all scores increased significantly, the Wilcoxon Signed Rank Test was used to demonstrate the difference between scores, and agreement for findings during cystometry was tested with Mann-Whitney U. RESULTS: A total of 68 women participated; 38 participants reported pain, 57 reported urgency, and 33 reported both symptoms. Pain and urgency scores significantly increased during cystometry (P < 0.0001). For participants reporting pain, suprapubic pain was rated significantly higher than urethral pain. Participants reporting both symptoms, felt more urgency than pain, and again pain more suprapubically than urethrally. Participants reporting only urgency scored suprapubic and urethral urgency similarly at all desires. CONCLUSIONS: Pain and urgency are well differentiated sensations and are felt at different locations although pain is seemingly easier localized. Neurourol. Urodynam. 36:620-625, 2017. © 2016 Wiley Periodicals, Inc.

Solvent-Dependent Pyranopterin Cyclization in Molybdenum Cofactor Model Complexes.

The conserved pterin dithiolene ligand that coordinates molybdenum (Mo) in the cofactor (Moco) of mononuclear Mo enzymes can exist in both a tricyclic pyranopterin dithiolene form and as a bicyclic pterin-dithiolene form as observed in protein crystal structures of several bacterial molybdoenzymes. Interconversion between the tricyclic and bicyclic forms via pyran scission and cyclization has been hypothesized to play a role in the catalytic mechanism of Moco. Therefore, understanding the interconversion between the tricyclic and bicyclic forms, a type of ring-chain tautomerism, is an important aspect of study to understand its role in catalysis. In this study, equilibrium constants (K(eq)) as well as enthalpy, entropy, and free energy values are obtained for pyran ring tautomerism exhibited by two Moco model complexes, namely, (Et4N)[Tp*Mo(O)(S2BMOPP)] (1) and (Et4N)[Tp*Mo(O)(S2PEOPP)] (2), as a solvent-dependent equilibrium process. Keq values obtained from (1)H NMR data in seven deuterated solvents show a correlation between solvent polarity and tautomer form, where solvents with higher polarity parameters favor the pyran form.