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Discovery and properties of enzymes for biocatalytic production of β-amino acids
No full textIn de natuur komen niet-proteïnogene β-aminozuren voor als vrije stoffen zoals osmoregulatoren en signaalmoleculen maar ook als bouwstenen voor vele secundaire metabolieten, bijvoorbeeld voor β-lactam antibiotica of in medicijnen tegen kanker, zoals taxol.
De synthese van β-aminozuren kan worden gedaan met chemische of met enzymatische processen. Het onderzoek van Ciprian Crismaru is vooral gericht op de enzymatische synthese van β-aminozuren, deze heeft aanzienlijke voordelen ten opzichte van de chemische processen, onder andere door hoge enantioselectiviteit, regio-selectiviteit, milde reactie condities en de kleine hoeveelheden katalysator die nodig zijn.
Een elegante manier om te zoeken naar enzymen die β-aminozuren kunnen omzetten is door middel van verrijkingsexperimenten. Crismaru beschrijft in zijn proefschrift de isolatie van 18 bacteriële stammen die β-alanine, β-glutamaat, β-asparagine, β-leucine, β-phenylalanine, D- asparaginezuur en β-tyrosine kunnen afbreken en ook het zoeken naar nieuwe deamineringsenzymen in sommige van deze culturen.
De enzymatische activiteit geassocieerd met β-phenylalanine afbraak was een aminotransferase (VpAT). Het gen dat voor VpAT codeert was gekloneerd en het enzym zijn biochemisch gekarakteriseerd, onder andere de substraatspecificiteit, het reactie-mechanisme en kristalstructuur zijn bepaald. Bovendien is een ander β-phenylalanine aminotransferase homoloog (MesAT) onderzocht voor vergelijkende functionele en structurele studies. In tegenstelling tot de voorgaande enzymatische processen is een totaal verschillend deamineringsmechanisme betrokken bij het metabolisme van β-valine. Een op een lyase-reactie gebaseerde deamineringsroute is gevonden en een genetische analyse van de veronderstelde β-valine reactiepad wordt gegeven. Een nieuw type lyase, dat reageert met het CoA-conjugaat van β-valine en gerelateerd is aan enoyl-CoA hydratasen katalyseert de deaminerings-reactie.
Deze bevindingen kunnen bijdragen aan de ontwikkeling van een moleculaire gereedschapskist voor de biokatalytische productie van β-aminozuren.
In nature, non-proteinogenic β-amino acids occur as free compounds such as osmoregulators and signaling molecules or as building blocks in various secondary metabolites such as β-lactam antibiotics or anticancer agents, like taxol.
Preparation of β-amino acids can be achieved in a chemical or enzymatic manner. In his research, Ciprian Crismaru focuses on the enzymatic synthesis, which has significant advantages over the chemical processes such as high enantioselectivity, high regioselectivity, mild reaction conditions and low amounts of catalyst used. Thus, enzyme reactions may provide environmental and economical benefits.
An elegant way to search for enzymes that convert β-amino acids is to perform enrichment experiments. Crismaru describes in his thesis the isolation of 18 bacterial strains that degrade β-alanine, β-glutamate, β-asparagine, β-leucine, β-phenylalanine, D-aspartic acid and β-tyrosine and the search for new deamination enzymes in some of these cultures.
The enzymatic activity associated to β-phenylalanine degradation was an aminotransferase (VpAT). The gene encoding VpAT was cloned and the enzyme was biochemically characterized with respect to substrate scope, reaction mechanism and crystal structure. Another β-phenylalanine aminotransferase homologue (MesAT) was investigated for comparative mechanistic and structural studies. In contrast, a totally different deamination mechanism was observed for β-valine. A lyase-based deamination route is proposed and a genetic analysis of the suspected β-valine pathway is presented. A novel type of lyase, acting on the CoA-conjugate of β-valine and related to enoyl-CoA hydratases, is proposed to catalyze the deamination reaction.
These findings should contribute to the development of a toolbox for the biocatalytic production of β-amino acids.
Influenza vaccine strategies that induce a cross-reactive cellular immune response
No full textDe begeleider en/of auteur heeft geen toestemming gegeven tot het openbaar maken van de scriptie.
The supervisor and/or the author did not authorize public publication of the thesis.
Probing the radio emission from air showers with polarization measurements
No full textThe emission of radio waves from air showers has been attributed to the so-called geomagnetic emission process. At frequencies around 50 MHz this process leads to coherent radiation which can be observed with rather simple setups. The direction of the electric field induced by this emission process depends only on the local magnetic field vector and on the incoming direction of the air shower. We report on measurements of the electric field vector where, in addition to this geomagnetic component, another component has been observed that cannot be described by the geomagnetic emission process. The data provide strong evidence that the other electric field component is polarized radially with respect to the shower axis, in agreement with predictions made by Askaryan who described radio emission from particle showers due to a negative charge excess in the front of the shower. Our results are compared to calculations which include the radiation mechanism induced by this charge-excess process.
Explicit simplicial discretization of distributed-parameter port-Hamiltonian systems
No full textSimplicial Dirac structures as finite analogues of the canonical Stokes–Dirac structure, capturing the topological laws of the system, are defined on simplicial manifolds in terms of primal and dual cochains related by the coboundary operators. These finite-dimensional Dirac structures offer a framework for the formulation of standard input–output finite-dimensional port-Hamiltonian systems that emulate the behavior of distributed-parameter port-Hamiltonian systems. This paper elaborates on the matrix representations of simplicial Dirac structures and the resulting port-Hamiltonian systems on simplicial manifolds. Employing these representations, we consider the existence of structural invariants and demonstrate how they pertain to the energy shaping of port-Hamiltonian systems on simplicial manifolds.
