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Monophosphate and Thiamine Pyrophosphate : a Quantumchemical Description

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Monophosphate and Thiamine Pyrophosphate : a Quantumchemical Description The coenzymes cyclic adenosine 3',5'-monophosphate and thiamine pyrophosphate : a quantumchemical description Citation for published version (APA): Scheffers - Sap, M. M. E. (1979). The coenzymes cyclic adenosine 3',5'-monophosphate and thiamine pyrophosphate : a quantumchemical description. Technische Hogeschool Eindhoven. https://doi.org/10.6100/IR25489 DOI: 10.6100/IR25489 Document status and date: Published: 01/01/1979 Document Version: Publisher’s PDF, also known as Version of Record (includes final page, issue and volume numbers) Please check the document version of this publication: • A submitted manuscript is the version of the article upon submission and before peer-review. There can be important differences between the submitted version and the official published version of record. People interested in the research are advised to contact the author for the final version of the publication, or visit the DOI to the publisher's website. • The final author version and the galley proof are versions of the publication after peer review. • The final published version features the final layout of the paper including the volume, issue and page numbers. Link to publication General rights Copyright and moral rights for the publications made accessible in the public portal are retained by the authors and/or other copyright owners and it is a condition of accessing publications that users recognise and abide by the legal requirements associated with these rights. • Users may download and print one copy of any publication from the public portal for the purpose of private study or research. • You may not further distribute the material or use it for any profit-making activity or commercial gain • You may freely distribute the URL identifying the publication in the public portal. If the publication is distributed under the terms of Article 25fa of the Dutch Copyright Act, indicated by the “Taverne” license above, please follow below link for the End User Agreement: www.tue.nl/taverne Take down policy If you believe that this document breaches copyright please contact us at: [email protected] providing details and we will investigate your claim. Download date: 25. Sep. 2021 THE COENZYMES CYCLIC ADENOSINE 3', 5' -MONOPHOSPHATE AND THIAMINE PYROPHOSPHATE A quantumchemical description M. M. E. SCHEPPERS-SAP CO-ENZYMEN CYCLISCH ADENOSINE 3 1 ,5 1 -MONOFOSFAAT EN C:.'fiAMINE PYROFOSFAAT. EEN QUANTUMCHEMISCHE BESCHRIJVING. Xaast water zijn proteinen (eiwitten) essentiële bestand­ delen van alle levende organismen, van de meest eenvoudige tot de meest complexe toe. In levende organismen hebben proteinen verschillende functies; ze treden op als: - e~zymen, dit zijn stoffen die scheikundige reacties kunnen versnellen of vertragen. Het zijn dus katalysatoren. - ~ntistoffen, die als wapen dienen in het arsenaal van verdedigingsmechanismen van organismen. - ~ou~stenen van lange eiwitketens. - :ransportmiddeZ, d.w.z. ze zijn verantwoordelijk voor het vervoer van belangrijke stoffen, o.a. zuurstof, in levende organismen. - scheikundige boodschappers. Een voorbeeld vormen de hor­ monen die chemische reacties laten plaatsvinden of op­ houden zodanig, dat levensprocessen mogelijk worden. :oals hierboven al is aangegeven, worden proteinen met katalytische activiteit enzymen genoemd. Vele enzymen hebben om werkzaam te kunnen zijn een, van proteinen ver­ schillend, deeltje nodig. Daar deze deeltjes mede verant­ Koordelijk zijn voor het totale reactieverloop noemt men ze co-enzymen. Het werk dat in dit proefschrift is beschre­ ven heeft betrekking op twee co-enzymen, namelijk cyclisch adenosine 3' ,5'-monofosfaat (afgekort: c-AMP) en thiamine pyrofosfaat (afgekort: TPP). CycZisch adenosine 3',5'-monofosfaat In hogere organismen, zoals de mens, treedt c-AMP op als tweede boodschapper van veel hormonen. Hormonen (eerste boodschappers) die een celwand niet kunnen passeren, zijn toch in staat processen in de cel te beïnvloeden door er voor te zorgen, dat via de wand van de cel de boodschap doorgegeven wordt, waardoor dan het c-AMP i<~ordt gevormd in de cel. Het c-AMP activeert of inactiveert dan op zijn beurt enzymen in de cel en is zo in staat indirect vele processen te regelen. Na het bewerkstelligen van de ge­ wenste effecten in de cel dient c-AMP uitgeschakeld te worden. Dit gebeurt 6f doordat het door de cel onveranderd \vordt uitgescheiden 6f doordat het door enzymen omgezet wordt in adenosine 5'-monofosfaat (afgekort: 5'-ANP). Deze laatste reactie wordt als volgt weergegeven: R 0 _::, 05'~~· 0--~p/ OH HO/ OH c-AMP water 5'-AMP R=adenine Bij de vorming van 5'-AMP uit c-AMP komt veel warmte vrij. De hoeveelheid die vrij komt is groter dan bij reacties van soortgelijke verbindingen. Met behulp van computerberekeningen aan eenvoudige molecuulmodellen van c-M4P en 5'-AMP (R = H, waterstof) is geprobeerd een verklaring te vinden voor die grotere hoeveelheid warmte. De berekeningen zijn gedaan aan een­ voudigere moleculen omdat de rekentijd anders veel te groot wordt. De gegevens verkregen uit de berekeningen tonen aan dat het warmte-effect kan worden toegeschreven aan twee factoren: 1) het verschil in ruimtelijke vorm van de vijfring in c-AMP en 2) het verschil in aanhechting van watermole­ culen (de stoffen zijn opgelost in water) aan verschil­ lende kanten van de deeltjes 5 '-AMP en c-AMP. In 5'-AMP kan zich een watermolecule bevinden tussen de zuurstofatomen (0) op positie 1' en 5'. Dit is in c-AMP niet mogelijk, omdat de afstand tussen deze twee atomen te groot is. :~iamine pyrofosfaat TPP is een algemeen voorkomend co-enzym in levende orga­ nismen. Het is een voor de mens noodzakelijke voedings­ stof ter voorkoming van beriberi (verlammingsziekte). TPP treedt op als co-enzym bij reacties van ketocarbonzuren (bijvoorbeeld: pyruvaat deeltje CH 3COCOO-), waarbij kool zuurgas vrijkomt. De manier waarop TPP functioneert is ontdekt door R. Breslow, die vaststelde dat het reactieve centrum (hier vinden de reacties plaats met andere stof­ fen) zich bevindt op het koolstofatoom (positie 2) tussen stikstof (N) en zwavel (S). Uit proeven door R. Ereslow uitgevoerd aan de vijfring van TPP en erop lijkende vijf­ ringen is gebleken, dat de vorming van een reactief cen­ trum op positie 2 bij een vijfring waarin S vervangen is door een stikstofatoom (N, imidazolium systeem) moeilijker verloopt dan bij de thiazolium ring (dit is de naam van de vijfring in TPP). Deze bevindingen zijn echter tegen- strijdig met spectrametrische gegevens van deze twee vijf­ ringen, waaruit men namelijk kan afleiden dat de vorming van het reactieve centrum in beide gevallen even snel zou moeten gaan. Aan eerder genoemde vijfringen en de te vormen vijfringen met een reactief centrum zijn computerberekeningen gedaan om te achterhalen welke factoren verantwoordelijk z n voor de, relatief gezien, grote snelheid waarmee bij het thiazolium systeem het reactieve centrum gevormd wordt. De gegevens tonen aan, dat het thiazolium systeem de electrenen (dit zijn de deeltjes die zorgen voor de bin- dingen tussen de atomen) die betrokken zijn bij de vorming van het reactieve centrum op een zodanige wijze heeft op­ geborgen, dat ze gemakkelijker te gebruiken zijn. M.M.E. Scheffers-Sap Berlicum, 14 december 1979 THE COENZYMES CYCLIC ADENOSINE 3', 5' -MONOPHOSPHATE AND THIAMINE PYROPHOSPHATE A quantumchemical description PROEFSCHRIFT ter verkrijging van de graad van doctor in de technische wetenschappen aan de Technische Hogeschool Eindhoven, op gezag van de rector magnificus, prof. ir. J. Erkelens, voor een commissie aangewezen door het college van dekanen in het openbaar te verdedigen op vrijdag 14 december 1979 te 16.00 uur door MARIA MARGARETHA ELISABETH SCHEFFERS-SAP geboren te Tilburg DRUK: WIBRD HELMONO DIT PROEFSCHRIFT IS GOEDGEKEURD DOOR DE PROMOTOREN PROF. DR. H.M. BUCK EN PROF. DR. U.K. PANDIT "Would you tell me, please, which way I ought to go from here?" "That depends a good deal on where you want to get to," said the Cat. "I don't much care where-" said Alice. "Then it doesn't matter which way you go," said the Cat. "-so long as I get somewhere," Alice added as an explanation. "Oh, you're sure to do that," said the Cat, "if you only walk long enough." uit Alice's Adventures in Wonderland Contents Chapter I General introduetion 1.1 Coenzymes 11 I.Z Cyelio adenosine 3',5'- monophosphate 12 I.3 Thiamine pyrophosphate 16 I.4 The va~idi of quantum- ohemioal ealoulations 17 Heferenoes 20 Chapl:er 11 Summary of the all-valenee methods used, the Extended-Hückel, CND0/2 and ab-initio method 11.1 Introduetion 21 II.Z The Extended-Hüekel method 1!.2.1 Theory 23 II.2.2 Parameters the ordinary and iterative EH calculations 25 II.3 The Complete NegZeet Differential Overlap method 11.3.1 Theory the CNDO method 26 II.3.2 Parametrization for the CND0/2 methad 29 II.3.3 The GEOMO program 30 11.4 Ab-initia calculations 31 11.5 Mulliken population ana is 32 II.6 Calculation of the solvation enthalpy 33 Heferences 36 Chapter 111 The solvent effect on the enthalpy of hydralysis of c-AMP 111.1 Introduetion 38 111.2 Geometriee of phoephate dieetere 41 111.3 The effeat of the solvent and the ribose ring puaker­ ing on the net enthalpies of hydralysis 111.3.1 Calaulation of net enthalpies of hydra­ lysis and net sol- vation enthalpies 46 111.3.2 Ribose ring puaker­ ing 51 111.4 Diecuesion 51 Referenaei and notes 55 Chapter IV , The influence of solvation and ribose ring puckering on the enthalpy of hydralysis of c-AMP IV.1 Hydragen bonding 58 1V.2 The water dimer 60 1V.3 Hydration sahemes of models of a-AMP • 5 1 -AMP and 3 '-AMP 62 1V.4 The aontribution of sol­ vation and ribose ring puakering to the net en­ thalpy of hydralysis of a-AMP 68 1V.S Hydragen bonding ae a model for the dynamias of enzyme­ aoenzyme aomplexes 69 Referenaes 72 Chapter V The acidity of thiamine pyro­ phosphate and related systems V.l IntPoduction V.1.1 Ristoriaal back- ground 74 V.1.2 Relation structure of TPP to the oata- lytio aativity 77 V.2 CND0/2 calculations on 1,3- azolium systems V.
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