Two methods were developed: the stacked method with particular relevance to low activities and large amounts of side-products including a cleaning step after every 12 th injection to improve the quality of the acquired data. The second method for the screening of natural enzymatic reactions, which generally has only few sideproducts, was run with 33 s injection interval allowing microtiter plate analysis within 50 min. Both systems were employed by screening two different enzymes and reactions in two biological systems demonstrating the applicability of the MISER-GC-MS system. For the YfeX catalysed carbene-transfer reaction a highly unusual variant with tryptophan as an axial ligand could be identified. For the screening of the chimera library of fungal unspecific peroxygenase (UPO) the system allowed the analysis of seven plates within a day resulting in new peroxygenase chimeras as catalysts. The additional R-script provides the user with quick a quality control and data evaluation, also taking into account the protein quantification based on a split-GFP assay. The demonstrated MISER-GC-MS technology can be implemented into any laboratory with a GC-MS equipped with an autosampler.