Ubiquitin-activating Enzyme 1-like 2 (UBE1L2), also known as ubiquitin-like modifier activating enzyme 6 (UBA6), is a 1052 amino acid (aa) member of the ubiquitin-activating (E1) enzyme family with a predicted molecular weight of 118 kDa. The mouse and rat UBE1L2/UBA6 orthologs share 88% aa sequence identity with the human protein. UBE1L2/UBA6 is expressed in vertebrate cells where four isoforms have been identified. UBE1L2/UBA6 is an activating enzyme for both ubiquitin and FAT10 via a similar molecular mechanism but has a higher affinity for FAT10 than for ubiquitin. UBE1L2/UBA6 contains an ATP-binding motif and an active site cysteine residue, Cys625 in humans, common to E1 enzymes. It shares 40% aa sequence identity with the related family member ubiquitin activating enzyme/UBE1. Similar to UBE1, UBE1L2/UBA6 can transfer activated ubiquitin to ubiquitin-conjugating (E2) enzymes including the UbcH5 isoforms and UbcH7. Unlike UBE1, which can transfer ubiquitin to the cell cycle-associated E2 enzyme, UbcH3, UBE1L2/UBA6 can transfer ubiquitin to Use1/UBE2Z, an E2 enzyme that cannot be charged with ubiquitin by UBE1. UBE1L2/UBA6-initiated covalent linkage of FAT10 to protein targets results in proteasomal degradation. UBE1L2/UBA6 is essential for embryonic development. One isoform, nUBE1L, is highly expressed in human testis and may play a role in spermatogenesis and male fertility.