The human ETFB gene encodes the Electron-transfer-flavoprotein, beta subunit, also known as ETF-β. Together with Electron-transfer-flavoprotein, alpha subunit, encoded by the 'ETFA' gene, it forms the heterodimeric Electron transfer flavoprotein (ETF). The native ETF protein contains one molecule of FAD and one molecule of AMP, respectively. First reports on the ETF protein were based on ETF isolated from porcine liver. Porcine and human ETF transfer electrons from mitochondrial matrix flavoenzymes to Electron transfer flavoprotein-ubiquinone oxidoreductase (ETF-QO) encoded by the ETFDH gene. ETF-QO subsequently relays the electrons via ubiquinone to complex III in the respiratory chain. The flavoenzymes that transfer electrons to ETF are involved in fatty acid beta oxidation, amino acid catabolism, choline metabolism, and special metabolic pathways. Defects in either of the ETF subunits or ETFDH cause multiple acyl CoA dehydrogenase deficiency (OMIM # 231680), earlier called glutaric acidemia type II. MADD is characterized by excretion of a series of substrates of the upstream flavoenzyes, e.g. glutaric, lactic, ethylmalonic, butyric, isobutyric, 2-methyl-butyric, and isovaleric acids. Evolutionary relationships ETF is an evolutionarily ancient protein with orthologues found in all kingdoms of life. ETFs are grouped into 3 subgroups, I, II, and III. The best studied group are group I ETFs that in eukaryotic cells are localized in the mitochondrial matrix space. Group I ETFs transfer electrons between flavoenzymes. Group II ETFs may also receive electrons from ferredoxin or NADH. Gene, expression, and subcellular localization The human ETFB gene encoding the beta subunit of ETF (ETF-β) is localized on chromosome 19 (19q13.3). It is composed of 6 exons. Little is known about its promoter and transcriptional regulation. Global expression analyses show that it is expressed at substantial levels in most tissues (PROTEOMICXS DB). ETF-β is posttranslationally imported into the mitochondrial matrix space, but it does not have a cleaved N-terminal mitochondrial targeting sequence. Posttranslational modifications and regulation Acetylation and succinylation of lysine residues and phosphorylation of serine and threonine residues in ETF-β have been reported in mass spectrometric analyses of posttranslational modifications P13804. Trimethylation of two lysines, Lys-200 and Lys-203, in ETF-β has been indicated to affect ETF activity. Electron transfer flavoprotein regulatory factor 1 (ETFRF1) has been identified as a protein that specifically binds ETF and this interaction has been indicated to inactivate ETF by displacing the FAD. Structure and interaction with redox partners As first shown for porcine ETF, one chain of ETF-β assembles with one chain of ETF-α,