RESUMO
Technologies for the engineering of biocatalysts for efficient synthesis of pharmaceutical targets have advanced dramatically over the last few years. Integration of computational methods for structural modeling, combined with high through put methods for expression and screening of biocatalysts and algorithms for mining experimental data, have allowed the creation of highly engineered biocatalysts for the efficient synthesis of pharmaceuticals. Methods for the synthesis of chiral alcohols and amines have been particularly successful, along with the creation of non-natural activities for such desirable reactions as cyclopropanation and esterification.
Assuntos
Biocatálise , Descoberta de Drogas/métodos , Indústria Farmacêutica , Enzimas e Coenzimas/metabolismo , Engenharia Metabólica , Preparações Farmacêuticas/síntese química , Álcoois/metabolismo , Aminas/química , Animais , Indústria Farmacêutica/métodos , Indústria Farmacêutica/tendências , Enzimas e Coenzimas/genética , Humanos , Engenharia Metabólica/métodos , Engenharia Metabólica/tendências , Preparações Farmacêuticas/isolamento & purificação , Preparações Farmacêuticas/metabolismo , Bibliotecas de Moléculas Pequenas/isolamento & purificação , Bibliotecas de Moléculas Pequenas/metabolismoRESUMO
Experimental data show that cholesterol can modulate central processes in the pathogenesis of Alzheimer's disease (AD). The epidemiological link between elevated plasma cholesterol at midlife and increased risk for AD and the possibility that 3-hydroxy-3-methylglutaryl-coenzym A reductase inhibitors (statins) may be protective against AD support a role of cholesterol metabolism in AD and have rendered it a potential therapeutic target in the treatment and prevention of the disease. The strong association of AD and AD endophenotypes with the APOE gene provides a genetic link between AD and cholesterol metabolism, because the apolipoprotein E (ApoE) is the most prevalent cholesterol transport protein in the central nervous system. Against this background several other genes with a role in cholesterol metabolism have been investigated for association with AD. In this review a compilation of genes related to cholesterol based on the information of the AmiGo gene ontology database is matched with the AlzGene database of AD candidate genes. 56 out of 149 (37.6%) genes with a relation to cholesterol metabolism have been investigated for association with AD. Given that only 660 out of about 23,000 (2.9%) genes have been assessed in hypothesis-driven candidate gene studies on AD, the cholesterol metabolic pathway is strongly represented among these genes. Among 34 cholesterol-related genes for which association with AD has been described APOE, CH25H, CLU, LDLR, SORL1 outstand with positive meta-analyses. However, it is unclear, if their association with AD is mediated by cholesterol-related mechanisms or by more specific direct effects of the respective proteins on Abeta metabolism.