5L46

Crystal structure of human dimethylglycine-dehydrogenase

Summary for 5L46

• Entry DOI: 10.2210/pdb5l46/pdb
• Descriptor: Dimethylglycine dehydrogenase, mitochondrial, FLAVIN-ADENINE DINUCLEOTIDE (3 entities in total)
• Functional Keywords: electron transfer, covalent flavinylation, oxidoreductase, one-carbon metabolism
• Biological source: Homo sapiens (Human)
• Cellular location: Mitochondrion: Q9UI17
• Total number of polymer chains: 2
• Total formula weight: 190190.12

Authors

Hromic, A.,Pavkov-Keller, T.,Gruber, K. (deposition date: 2016-05-25, release date: 2016-08-17, Last modification date: 2024-01-10)

Primary citation

Augustin, P.,Hromic, A.,Pavkov-Keller, T.,Gruber, K.,Macheroux, P.
Structure and biochemical properties of recombinant human dimethylglycine dehydrogenase and comparison to the disease-related H109R variant.
Febs J., 283:3587-3603, 2016

PubMed Abstract: The human dimethylglycine dehydrogenase (hDMGDH) is a flavin adenine dinucleotide (FAD)- and tetrahydrofolate (THF)-dependent, mitochondrial matrix enzyme taking part in choline degradation, one-carbon metabolism and electron transfer to the respiratory chain. The rare natural variant H109R causes dimethylglycine dehydrogenase deficiency leading to increased blood and urinary dimethylglycine concentrations. A detailed biochemical and structural characterization of hDMGDH was thus far hampered by insufficient heterologous expression of the protein. In the present study, we report the development of an intracellular, heterologous expression system in Komagataella phaffii (formerly known as Pichia pastoris) providing the opportunity to determine kinetic parameters, spectroscopic properties, thermostability, and the redox potential of hDMGDH. Moreover, we have successfully crystallized the wild-type enzyme and determined the structure to 3.1-Å resolution. The structure-based analysis of our biochemical data provided new insights into the kinetic properties of the enzyme in particular with respect to oxygen reactivity. A comparative study with the H109R variant demonstrated that the variant suffers from decreased protein stability, cofactor saturation, and substrate affinity.

PubMed: 27486859
DOI: 10.1111/febs.13828

Experimental method

X-RAY DIFFRACTION (3.09 Å)