Abstract α-Methylacyl-CoA racemase (Amacr) is an auxiliary enzyme of β-oxidation and participates in the elimination of methyl-branched fatty acids in peroxisomes and in mitochondria and in the synthesis of bile acids in peroxisomes. Amacr catalyzes in reversible manner the isomerization of fatty acyl-CoA esters with a methyl group in the R-configuration to the corresponding S-configuration, which allows them to serve as substrates for the next reaction in their metabolism. The substrates of Amacr include the acyl-CoA esters of 2R-pristanic acid, a metabolite derived from phytol, and 25R-THCA and 25R-DHCA (tri- and dihydroxycholestanoic acid), the bile acid intermediates derived from cholesterol. AMACR-deficiency in humans results in the accumulation of R-isoforms of its substrates. Patients with adult onset AMACR-deficiency suffer from neurological disorders. The more severe infantile form of the deficiency is characterized by liver disease. Amacr-deficient mice show a bile acid pattern similar to that of human patients with accumulation of bile acid intermediates in their body. In contrast to humans, Amacr-deficient mice are clinically symptomless on a regular laboratory chow diet. Supplementation of phytol in their diet triggers the disease state with liver abnormalities. In this study it was shown that in spite of the disruption of a major metabolic pathway, Amacr-deficient mice are able to readjust their cholesterol and bile acid metabolism to a new balanced level allowing them to live a normal life span. A double knockout mouse model deficient in Amacr and MFE-1 (peroxisomal multifunctional enzyme type 1) was generated in this work. Characterization of this mouse line showed that MFE-1 can contribute to peroxisomal side-chain shortening of C27 bile acid intermediates in both Amacr-dependent and Amacr-independent pathways. In addition, this work confirmed that Amacr-deficient mice are unable to thrive when phytol is supplemented in their chow. The main cause of death was liver failure accompanied by kidney and brain abnormalities. The detoxification of phytol metabolites in liver is accompanied by activation of multiple pathways and Amacr-deficient mice are not able to respond adequately. The results of this study emphasize the indispensable role of Amacr in detoxification of α-methyl branched fatty acids. / Tiivistelmä α-Metyyliasyyli-koentsyymi-A-rasemaasi (Amacr) osallistuu metyyli-haarautuvien rasvahappojen eliminointiin peroksisomeissa ja mitokondrioissa ja sappihappojen synteesiin kolesterolista peroksisomeissa. Amacr katalysoi käänteisesti rasvahappojen asyyli-koentsyymi-A-estereiden isomerisaatio-reaktiota, jossa stereokemiallisesti R-asemassa oleva metyyliryhmä siirtyy S-asemaan. Tämä on edellytys eliminointiketjun seuraavan reaktion tapahtumiselle. Amacr-entsyymin substraatteja ovat fytolin aineenvaihdunnassa syntyvän 2R-pristaanihapon ja kolesterolista sappihapposynteesireitin välituotteina syntyvien 25R-trihydroksikolestaanihapon ja 25R-dihydroksikolestaanihapon (25R-THCA ja 25R-DHCA) asyyli-koentsyymi-A-esterit. Ihmisellä Amacr-entsyymin puutos johtaa R-muodossa olevien substraattien kertymiseen, joka aiheuttaa neurologisia oireita aikuisiässä alkavassa sairauden muodossa. Lapsuusiässä alkavassa tautimuodossa potilaille kehittyy vakava maksasairaus. Tutkimuksen tulokset osoittivat, että Amacr-poistogeenisten hiirten elinikä ei lyhene huolimatta yhden tärkeän aineenvaihduntareitin estymisestä. Tämä on hyvä esimerkki siitä, kuinka nisäkäs pystyy mukauttamaan kolesteroli- ja sappihappoaineenvaihduntaansa vastaamaan muuttunutta tilannetta aineenvaihdunnassa. Tässä työssä tuotettiin myös kaksoispoistogeeninen hiirimalli, jonka Amacr- ja peroksisomaalinen monitoiminnallinen entsyymi tyyppi 1- (MFE-1) entsyymit ovat toimimattomat. Tämä hiirimalli paljasti, että MFE-1 pystyy osallistumaan 27:ää hiiltä sisältävien sappihappovälituotteiden sivuketjun lyhentämiseen sekä Amacr entsyymin kanssa että ilman sitä. Työn tulokset myös osoittivat, että Amacr-poistogeeniset hiiret eivät ole elinkykyisiä, jos niiden ravinto sisältää fytolia. Maksan toiminnanvajaus oli näiden hiirten tärkein kuolinsyy, mutta hiirten munuaisten ja aivojen kudosrakenteissa oli myös muutoksia. Maksassa fytolin metaboliittien vaarattomaksi tekeminen aiheuttaa villityypin hiirillä useamman aineenvaihduntareitin aktivoitumisen, mutta Amacr-poistogeeniset hiiret eivät pysty reagoimaan tähän samalla tavalla. Tämä työ osoittaa, että Amacr-entsyymin elintärkeä tehtävä on osallistua ravinnon mukana elimistöön joutuvien α-metyylihaarautuvien rasvahappojen eliminaatioon.

L'alcool est une des principales causes de maladie du foie en Europe avec peu d'options thérapeutiques. Parmi les consommateurs d'alcool, seul certains patients vont évoluer vers des formes sévères d'atteinte hépatique et le microbiote intestinal a été identifié comme cofacteur de cette susceptibilité individuelle. Il interagit avec le foie notamment via la production de métabolites bactériens tels que les acides biliaires secondaires.L'objectif de ce travail a été dans un premier temps d'analyser le microbiote intestinal, au sein d’une cohorte de patients alcooliques à différents stades de la maladie alcoolique du foie, et d’étudier sa relation avec les acides biliaires. Dans un deuxième temps, ce projet avait pour but d’étudier s’il était possible d'améliorer l'atteinte hépatique liée à l'alcool, en modulant le microbiote intestinal, dans un modèle animal de maladie alcoolique du foie.Les patients avec une atteinte hépatique sévère liée à l'alcool ont un profil d’acides biliaires plus hydrophobe, et donc plus toxique, associé à une dysbiose et à des modifications des fonctions bactériennes. Ces modifications des fonctions bactériennes participent à la gravité de la maladie. La modulation du microbiote par la pectine, un prébiotique, permet de prévenir mais également de faire régresser les lésions hépatiques chez la souris. Les effets protecteurs de la pectine sont corrélés avec le métabolisme du tryptophane.Ce travail de thèse montre que le microbiote intestinal et ses métabolites sont une cible thérapeutique potentielle dans la maladie alcoolique du foie. Il ouvre la porte à la réalisation d'essais cliniques chez l'homme dans lesquels nous pourrions limiter la progression des lésions hépatiques liées à l'alcool en contrôlant le microbiote intestinal grâce à l’utilisation de la pectine ou du métabolisme du tryptophane. / Alcohol is one of the main causes of alcoholic liver disease in Europe with few therapeutic options. Among alcohol consumers, only a part of these patients will develop severe liver lesions. This individual susceptibility is driven by intestinal microbiota. Intestinal microbiota interacts with the liver through the production of bacterial metabolites including the secondary bile acids.The aim of my project, was firstly to study the relationship between the intestinal microbiota and the bile acids composition depending on the severity of alcoholic liver disease in a cohort of alcoholic patients. Secondly, I assessed the improvement of alcohol induced liver lesions by changing the intestinal microbiota in a mouse model of alcoholic liver disease.Patients with a severe form of alcoholic liver disease display a higher hydrophobic bile acid pool, more toxic, associated with a specific dysbiosis and changes in the bacterial functions. Changing the intestinal microbiota by using pectin, a prebiotic, prevents and reverts alcohol induced liver injury in mice. These protective effects of pectin involve changes in the tryptophan metabolism.In conclusion, these studies highlight that the intestinal microbiota and its metabolites are potential therapeutic targets for alcoholic liver disease. Moreover, pectin as an alimentary product could be proposed in the management of alcoholic liver disease in humans.

<p>Doktorska disertacija razmatra solubilizaciju holesterola pomoću okso derivata žučnih kiselina, upoređuje okso derivate žučnih&nbsp; kiselina&nbsp; sa hidroksi-derivatima istih u solubilizaciji holesterola i ispituje uticaj okso derivata na vijabilnost ćelijske membrane.&nbsp; Takođe, ispituje pKa vrednost različitih okso-derivata žučnih kiselina sa ciljem da se odredi kiselinska konstanta ovih slabih organskih kiselina. Cilj određivanja pKa vrednosti jeste determinacija rastvorljivosti žučnih kiselina. Kada se primenjuju oralno u raznim farmaceutsko-tehnolo&scaron;kim formulacijama, one se primenjuju u obliku soli, koje su rastvorne u vodi. Međutim, u kiseloj sredini želuca može doći do taloženja žučne kiseline i do daljeg sprečavanja delovanja soli žučne kiseline kao solubilizatora određenih farmacutski aktivnih supstanci. Doktorska disertacija ispituje i kritičnu micelarnu koncentraciju me&scaron;ovitih micela natrijumovih soli 3 žučne kiseline (holne, deoksiholne i 7-oksodeoksiholne kiseline) i natrijum-dodecil-sulfata u različitim molskim udelima na temperaturama od 0 do 50&deg;C pomoću spektrofluorifotometra pirenskom metodom.</p> / <p>The PhD thesis discusses solubilization of cholesterol by using oxo derivatives of bile acids and compares it&nbsp; with the hydroxy-derivatives of the same in the solubilization of cholesterol, and examines the impact of the oxo derivatives to the viability of the cell membrane. Also, the pKa value of different&nbsp; tested oxo-derivatives of&nbsp; bile acids is determined. The aim of determining the pKa values is to determine the solubility of bile acids. When administered orally in various pharmaceutical-technological formulations, they are applied in the form of salts, that are soluble in water. However, the acidic medium of the stomach may cause precipitation of a bile salt and further prevent the action of bile acid salts as a solubilizers of specific pharmaceutically active substances. The PhD&nbsp;&nbsp; thesis examined the the critical micelle concentration of the mixed micelles of sodium salt of 3 bile acid (cholic, deoxycholic, and 7-oksodeoksiholne acid) and sodium dodecyl sulphate at various temperatures, the mole fractions ranging from 0 to 50 &deg;C using the method of spectrofluoriphotometry by pirene as a probe molecule.</p>

<p>Surfaktanti imaju značajnu primenu u farmaciji i medicini. Ove supstance se primenjuju u farmakoterapiji, koriste se za solubilizaciju hidrofobnih lekova, a pojedina ispitivanja pokazuju da mogu unaprediti bioraspoloživost određenih aktivnih supstanci. U poslednje vreme se sve vi&scaron;e pažnje posvećuje ispitivanju sme&scaron;a surfaktanata, po&scaron;to je utvrđeno da sistemi dva ili vi&scaron;e surfaktanta često pokazuju poželjnija svojstva od pojedinačnih surfaktanata za aplikaciju u farmaciji i medicini. U ovoj disertaciji su ispitivani binarni sistemi osam anjona žučnih kiselina i dva nejonska surfaktanta (polisorbat 40 i polisorbat 80). Ciljevi su određivanje vrednosti kritičnih micelarnih koncentracija ispitivanih sme&scaron;a surfaktanta, utvrđivanje međudejstva između različitih surfaktanta u njihovim me&scaron;ovitim micelama, kao i ispitivanje uticaja stukture ispitivanih surfaktanata na fizičko-hemijske karakteristike me&scaron;ovitih micela. Rezultati pokazuju da ispitivane sme&scaron;e imaju znatno niže vrednosti kritičnih micelarnih koncentracija od anjona žučnih kiselina. Sme&scaron;e anjona žučnih kiselina i polisorbata 40 imaju manje vrednosti eksperimentalnih kritičnih micelarnih koncentracija, od izračunatih, idealnih, vrednosti, &scaron;to ukazuje na postojanje sinergističkih interakcija u me&scaron;ovitim micelama. Sme&scaron;e anjona žučnih kiselina i polisorbata 80 imaju uglavnom veće vrednosti kritičnih micelarnih koncentracija od idealnih vrednosti, &scaron;to može biti posledica postojanja antagonističkih interakcija između gradivnih jedinica me&scaron;ovitih micela. Vrednosti interakcija, koje dovode do neidealnog pona&scaron;anja sistema surfaktanata, su određene računanjem vrednosti interakcionog parametra, &beta;_1,2, prema regular solution theory. Sistemi anjona žučnih kiselina i polisorbata 40 imaju negativne vrednosti interakcionog parametra, dok sistemi anjona žučnih kiselina i polisorbata 80 imaju uglavnom pozitivne vrednosti interakcionog parametra. Poređenjem fizičko-hemijskih parametara me&scaron;ovitih micela je utvrđeno da postojanje privlačnih međudejstava između hidrofilnih delova različitih surfaktanata najverovatnije potiče od vodoničnih veza koje se formiraju između hidrofilnih grupa anjona žučnih kiselina i polioksietilenskih delova. Pozitivne vrednosti &beta;_1,2 parametra su najverovatnije posledica sterno krute cis dvostruke veze oleinske kiseline u molekulu polisorbata 80, usled čega se lipofilni deo ovog nejonskog surfaktanta teže pakuje u jezgru me&scaron;ovitih micela. Pretpostavlja se da zbog toga dolazi do formiranja dimera anjona žučnih kiselina u me&scaron;ovitim micelama u kojima se javljaju odbojne interakcije između negativno naelektrisanih karboksilatnih grupa.</p> / <p>Surfactants have important application in pharmacy and medicine. These substances are applied in pharmacotherapy, they are used for hydrophobic drug solubilisation, and certain investigations indicate they can improve bioavailability of certain active substances. Lately, investigations of surfactant mixtures have gained a lot of attention, since it was found that systems of two or more surfactants often show more desirable properties than the individual surfactants, for application in pharmacy and medicine. In this dissertation, binary systems of eight bile acid anions and two nonionic surfactants (polysorbate 40 and polysorbate 80) were investigated. The aims were to determine values of critical micelle concentrations of investigated surfactant mixtures, interactions between different surfactants in their mixed micelles, and to investigate the influence of the structure of investigated surfactants on physico-chemical characteristics of mixed micelles. The results indicate that investigated mixtures have significantly lower values of critical micelle concentrations than bile acid anions. Mixtures of bile acid anions and polysorbate 40 have&nbsp; lower values of experimentally obtained critical micelle concentrations than the calculated, ideal, values, indicating the existence of synergistic interactions in mixed micelles. Mixtures of bile acid anions and polysorbate 80 have mainly higher values of critical micelle concentrations than the ideal values, what could be due to the existence of antagonistic interactions between building units of mixed micelles. The values of the interactions, attributing to the nonideal behaviour of the surfactant systems were obtained by calculating the values of the interaction parameter, &beta;1,2 , according to the regular solution theory. Systems of bile acid anions and polysorbate 40 have negative values of the interaction parameter, while systems of bile acid anions and polysorbate 80 have mainly positive values of interaction parameter. By comparing the physico-chemical parameters of mixed micelles, it was determined that existence of attractive interactions between hydrophilic parts of different surfactants most probably originates from the hydrogen bonds, which are formed between hydrophilic groups of bile acid anions and polyoxyethylene parts. Positive values of &beta;1,2 parameter are most probably due to sterically rigid cis double bond of oleic acid in polysorbate 80 molecule, causing the lipophilic tail of this nonionic surfactant to pack less easily in the core of mixed micelles. It is hypothesised that this influences formation of dimers of bile acid anions in mixed micelles, where repulsive interactions emerge between negatively charged carboxylate groups.</p>

Bile acids are the end products of cholesterol metabolism and are important biological surfactants. The curved shape of their chains allows the cyclization of molecules, and the formation of a supramolecular structure. The goal of this thesis was to study the electrochemical and adsorption behavior of selected bile acids: lithocholic, deoxycholic and cholic acids. The measurements were carried out in the medium Brittonův-Robinson buffer:methanol in the ratio 9:1 using cyclic voltammetry and AC voltammetry methods and measuring the dependence of the differential capacitance Cd on the applied potential E. A hanging mercury drop electrode was used as a working electrode. The measurements showed that bile acids are adsorbed on the surface of the electrode and organizing themselves in self assembled monolayers (SAM). In our case we have observed formation of 2D condensed layers as specific form of SAM. Transfer techniques were used to demonstrate bile acid adsorption. A study of the behavior of lithocholic acid as a function of different pH values showed that only at pH 10.0 to 12.0 2D 2D condensation occurs, i. e. that at pH values in the range of 2.0 to 9.0 it is another type of adsorption. On AC voltammograms, there are a maximum of two areas in which peaks occur: the first is around -0.2 V and the...

This master's thesis contains a study of electrochemical processes of selected bile acids possessing 7 hydroxyl group (cholic, chenodeoxycholic and −muricholic). The measurements were performed on boron−doped diamond electrode in the non-aqueous medium of acetonitrile and perchloric acid (water content 0.55 %) by cyclic voltammetry. It is known that the electrochemical activity of 7 bile acids is increased by a dehydration reaction between perchloric acid and the 7 bile acid. The subject of the study was the stability of the voltammetric response of chemically activated bile acids in the region of negative potentials. It was found that the presence of oxygen in the measured solution is an important factor for obtaining the cathodic signal of 7 bile acids. It probably performs a regenerative function; the product of the electrochemical reduction is re-oxidized in its presence, which leads to an increase in the voltammetric response. At the same time, it is important that the direction of the scan in cyclic voltammetry first proceeds to positive values. A potential of +2.0 V (vs. Ag/AgNO3 in acetonitrile) must be reached for the HO● radicals to be formed. It is these radicals that presumably lead to the formation of the product(s) of bile acids electrochemical oxidation that can be subsequently...

The gut microbiota plays a major part in maintaining the health of a human host. Countless of crucial functions in the body, including immune responses, cell signaling and energy metabolism to name a few, are conducted by the gut microbiota and its metabolites. Accordingly, it is of interest to gain knowledge on what can alter the gut microbiota, as these alterations by extension can give rise to adverse health effects. In this study, the impact of polychlorinated biphenyl (PCB)- and organochlorine pesticide (OCP) exposure on tricarboxylic acid (TCA) cycle metabolites, short-chain fatty acids (SCFAs) and bile acids, as well as other polar and semi-polar metabolites, which are all related to the gut microbiota, were investigated. An in vitro fermentation of faecal samples exposed to a PCB/OCP mixture was performed, and liquid chromatography-time of flight mass spectrometry (LC-qToF-MS) targeted and non-targeted approaches were applied to the extracts. The results obtained suggested that PCBs and OCPs most likely have an effect on the levels of several features of the gut metabolome with either increased or decreased levels upon exposure. Bile acids and TCA metabolites appear to follow a trend of decreasing levels, while no apparent effects could be seen for the SCFAs. Furthermore, distinct concentrations of the PCB/OCP mixture appear to induce different changes in gut microbiota functioning, which highlights the importance of performing dose-response studies when exploring biological effects of these compounds. The identification of different metabolite profiles during fermentation also allows for the possibility of further investigation of potential biomarkers to assess PCB/OCP exposure.

Bile acids are crucial for the uptake of dietary lipids and can shape the gut-microbiome composition. This latter function is associated with the toxicity of bile acids and can be modulated by bile acid modifying bacteria such as Eggerthella lenta, but the molecular details of the interaction of bacteria depending on bile acid modifications are not well understood. In order to unravel the molecular response to bile acids and their metabolites, we cultivated eight strains from a human intestinal microbiome model alone and in co-culture with Eggerthella lenta in the presence of cholic acid (CA) and deoxycholic acid (DCA). We observed growth inhibition of particularly gram-positive strains such as Clostridium ramosum and the gram-variable Anaerostipes cacae by CA and DCA stress. C. ramosum was alleviated through co-culturing with Eggerthella lenta. We approached effects on the membrane by zeta potential and genotoxic and metabolic effects by (meta)proteomic and metabolomic analyses. Co-culturing with Eggerthella lenta decreased both CA and DCA by the formation of oxidized and epimerized bile acids. Eggerthella lenta also produces microbial bile salt conjugates in a co-cultured species-specific manner. This study highlights how the interaction with other bacteria can influence the functionality of bacteria.

Les polymères amphiphiles sont largement utilisés pour les applications biomédicales et pharmaceutiques. Afin d’améliorer les chances de biocompatibilité des nouveaux polymères que nous voulons développer, nous avons utilisé des composés naturels, les acides biliaires, comme produits de départ dans la synthèse de ces polymères. De nouveaux polymères anioniques amphiphiles dérivés de l’acide cholique ont été préparés par polymérisation radicalaire par transfert d’atomes. Par un contrôle rigoureux des conditions de polymérisation, des bras de poly(acide acrylique) de différentes longueurs ont été greffés sur le squelette de l’acide cholique. L’architecture moléculaire des polymères a été étudiée par spectroscopie 1H RMN et par spectrométrie de masse. Ces polymères en étoile formés par l’acide biliaire modifié sont capables de s’agréger dans l’eau même si les groupements hydroxyles ont été remplacés par des segments plus volumineux. Il a été observé que les liaisons ester entre le polymère et le cœur d’acide cholique sont sensibles à l’hydrolyse en solution aqueuse. Pour remédier au problème de stabilité en solution aqueuse et pour avoir, en même temps, des bras hydrophiles non ioniques et biocompatibles, de l’oxyde d’éthylène a été polymérisé sur l’acide cholique par polymérisation anionique. Les liaisons éther formées entre le polymère et les groupements hydroxyles de l’acide biliaire sont plus stables que les liaisons ester sur le polymère de poly(acide acrylique). Les conditions de réaction de la polymérisation anionique ont été optimisées et ont donné des polymères aux architectures et aux masses molaires contrôlées. Les nouveaux polymères forment des agrégats sphériques tel qu’observé par microscopie électronique à transmission avec des échantillons préparés par la méthode de fracture à froid. Leur morphologie est différente de celle des agrégats cylindriques formés par les acides biliaires. Avec la méthode optimisée pour la polymérisation anionique, l’éther d’allyle et glycidyle a été polymérisé sur un dérivé d’acide cholique, suivi par une thiolation des liaisons doubles pour introduire l’amine ou l’acide sur la chaîne polymère. Cette addition radicalaire est efficace à plus de 90%. Les polymères qui en résultent sont solubles dans l’eau et s’agrègent à une certaine concentration critique. Il est particulièrement intéressant d’observer la thermosensibilité des polymères ayant des groupements amine, laquelle peut être modulée en acétylant partiellement les amines, donnant des points nuages entre 15 et 48°C. / Amphiphilic polymers are very useful in biomedical and pharmaceutical applications. To improve the biocompatibility of such polymers, we chose to use natural compounds such as bile acids as the starting material in the synthesis of the polymers. New anionic polymers have been prepared by atom transfer radical polymerization. Poly(acrylic acid) arms of various lengths have been grafted onto a bile acid core. The molecular architecture has been confirmed by 1H NMR spectroscopy and by mass spectrometry. The star polymers obtained from modified bile acid can aggregate in water, even though the hydroxyl groups were replaced by bulkier chains. The ester linkages between the polymers and the bile acid core are prone to hydrolysis in aqueous solutions. In order to improve the stability of the polymers in aqueous solutions and to introduce neutral and biocompatible hydrophilic arms, ethylene oxide has been polymerized onto a cholic acid core by anionic polymerization. The ether linkages formed between the hydroxyl groups of the bile acid and the poly(ethylene glycol) are more stable than the ester linkages formed with the poly(acrylic acid) polymers. The reaction conditions for the anionic polymerization have been optimized and provided well-defined polymers with narrow molecular weight distributions. The new polymers formed spherical aggregates as shown by transmission electron microscopy with samples prepared by the freeze-fracture technique. Their morphology is different from those of the cylindrical aggregates formed by bile salts. With the optimized method for anionic polymerization, allyl glycidyl ether was grafted onto a derivative of cholic acid, followed by thiolation, a radical addition, of the allyl groups to introduce amine or carboxylic acid groups to the polymer chains. This radical addition had an efficiency of more than 90%. The resulting polymers were water-soluble and were found to aggregate above a certain critical concentration. It is particularly interesting to observe thermosensitivity of the star polymers bearing amine groups. The thermosensitivity of such polymers can be further tuned by partial acetylation of the amine groups, yielding polymers with cloud points in the temperature range from 15 to 48°C.

Les matériaux utilisés pour les applications biomédicales doivent être biocompatibles, et idéalement biodégradables. Les acides biliaires proviennent de sources naturelles et sont présents dans le corps humain. De plus, les polyetsers composés en partie de ces molécules possèdent des liens hydrolysables, une mémoire de forme thermique, et leur flexibilité peut être variée. Jusqu’à présent, la synthèse de ces matériaux exigeait l’utilisation de catalyseurs contenant des métaux de transition lourds pour l’étape de macrocyclisation. Puisque la polymérisation par ouverture de cycle nécessite des précurseurs cycliques, l’étape de lactonisation fut réalisée par voie enzymatique, au lieu d’utiliser des catalyseurs à plus grande toxicité. De plus, une seule étape enzymatique a pu remplacer deux étapes de synthèse organique, avec un rendement de 58 % et l’obtention d’un matériel transparent. Ces macrocycles nouvellement obtenus ont par la suite été polymérisés par ouverture de cycle, de façon similaire à la technique élaborée par notre groupe en 2013, tout en optimisant la durée de réaction. En 15 heures, une masse molaire relativement grande de 40 000 g/mol fut obtenue, tout en maintenant la dispersité sous 1.4 et la température de transition vitreuse à 12 °C. Pour valider le principe de cyclisation et de polymérisation enzymatique, les conditions optimales pour combiner l’acide thapsique et le 1,10-decanediol furent préalablement déterminées. Entre autres, la durée de réaction et la quantité d’enzyme nécessaire furent analysées. Les polymères semi-crystallins obtenus possèdent aussi de grandes masses molaires et de basses dispersités. Or, il est possible d’utiliser un enzyme à la fois pour la fermeture et pour l’ouverture de cycle de molécules rigides à cœur stéroïdal, telles que les acides biliaires. Cette synthèse permet la production de matériaux plus biocompatibles, tout en favorisant plusieurs principes de chimie verte. / Materials used in biomedical applications need to be biocompatible and ideally biodegradable. Bile acids are natural occurring compounds found in humans, and their polyesters possess hydrolyzable bonds, thermal shape memory and tunable flexibility. Until now, the synthetic pathway to obtain such materials required transition metal catalysts for the macrocyclization step, which is necessary to perform ring-opening polymerization (ROP). To circumvent the need for such catalysts, enzymatic ring closing was performed using lipases. Conveniently, two synthetic steps were replaced with a single step, using a renewable and reusable catalyst, with 58 % yield and a colorless product. The bile acid-containing macrocycles were then enzymatically polymerized as described in our previous work, while optimizing the reaction time. In 15 hours, relatively high Mw of 40 000 g/mol were obtained, while maintaining the dispersity ≤ 1.4 and a glass transition temperature of about 12 °C. As a proof-of-concept, conditions for the enzymatic ring closure of thapsic acid with 1,10-decanediol were determined beforehand. While optimizing for enzyme amount and reaction time, enzymatic ROP conditions to obtain di- and tetralactones from these monomers were established. The resulting semi-crystalline polymers also possess relatively high molecular weight and low dispersity. Hence, the use of lipases for both ring-closing and ring-opening reactions now shows potential for large, rigid moieties in addition to more mobile structures, using the same enzyme. This is a step towards the production of more biocompatible polymers, with a synthetic pathway that follows many green chemistry principles.