Abstract
Enzymes in the transcarbamylase family catalyze the transfer of a carbamyl group from carbamyl phosphate (CP) to an amino group of a second substrate. The two best-characterized members, aspartate transcarbamylase (ATCase) and ornithine transcarbamylase (OTCase), are present in most organisms from bacteria to humans. Recently, structures of four new transcarbamylase members, N-acetyl-l-ornithine transcarbamylase (AOTCase), N-succinyl-l-ornithine transcarbamylase (SOTCase), ygeW encoded transcarbamylase (YTCase) and putrescine transcarbamylase (PTCase) have also been determined. Crystal structures of these enzymes have shown that they have a common overall fold with a trimer as their basic biological unit. The monomer structures share a common CP binding site in their N-terminal domain, but have different second substrate binding sites in their C-terminal domain. The discovery of three new transcarbamylases, l-2,3-diaminopropionate transcarbamylase (DPTCase), l-2,4-diaminobutyrate transcarbamylase (DBTCase) and ureidoglycine transcarbamylase (UGTCase), demonstrates that our knowledge and understanding of the spectrum of the transcarbamylase family is still incomplete. In this review, we summarize studies on the structures and function of transcarbamylases demonstrating how structural information helps to define biological function and how small structural differences govern enzyme specificity. Such information is important for correctly annotating transcarbamylase sequences in the genome databases and for identifying new members of the transcarbamylase family.
Highlights
The transfer of a carbamyl group from carbamyl phosphate (CP) to a nitrogen atom of another molecule is catalyzed by a family of enzymes termed transcarbamylases (Figure 1) of which aspartate transcarbamylase (ATCase) and ornithine transcarbamylase (OTCase) are the best-known members
The present review focuses on a comparison of all known and unknown members of the transcarbamylase family
These structural models suggest that the D250 residue within the HDLP motif (Saccharothrix mutabilis diaminopropionate transcarbamylase (DPTCase) numbering), which is a characteristic feature in DPTCase and diaminobutyrate transcarbamylase (DBTCase) sequences [70], will likely interact with the α-amino group of the second substrate and residue R212 from the equivalent 240’s loop may be involved in anchoring the carboxyl group of that substrate
Summary
The transfer of a carbamyl group from carbamyl phosphate (CP) to a nitrogen atom of another molecule is catalyzed by a family of enzymes termed transcarbamylases (Figure 1) of which aspartate transcarbamylase (ATCase) and ornithine transcarbamylase (OTCase) are the best-known members. Functional assignment was confirmed by catalytic studies and structure determination [24] The presence of the latter enzyme suggests that B. fragilis and some other bacteria with this unique protein have a novel arginine biosynthetic pathway that uses succinylated derivatives as intermediates [24]. The liganded and unliganded structures indicate that the active subunit is trimeric, similar to anabolic OTCase, AOTCase and SOTCase [29,30]. E. coli ATCase is one of the best structurally characterized enzymes Most of these structures are of the dodecameric holoenzyme, which consists of two catalytic trimers and three regulatory dimers, and is sensitive to allosteric effectors [5,37,38,39]. The structures clearly demonstrate that CP is the substrate for carbamylation, the second substrate and the biological function of this protein remain unknown [32]
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