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From Genome to Structure and Back Again: A Family Portrait of the Transcarbamylases.

Shi D, Allewell NM, Tuchman M - Int J Mol Sci (2015)

Bottom Line: 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.

View Article: PubMed Central - PubMed

Affiliation: Center for Genetic Medicine Research, Children's National Medical Center, the George Washington University, Washington, DC 20010, USA. dshi@childrensnational.org.

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.

No MeSH data available.


Related in: MedlinePlus

Higher oligomeric structure of ATCase. (A) R-state of Escherichia coli ATCase showing the dodecameric structure with two catalytic trimers (shown in red, magenta and cyan) at the top and bottom, and three regulatory dimers (shown in grey and tints) in the equator; (B) T-state of E. coli ATCase; (C) Structure of Aquifex aeolicus ATCase in complex with dehydroorotase. Two catalytic trimers located at the top and bottom are completely separated by three dehydroorotase dimers in the middle. Left: viewed perpendicular to three-fold axis; right: viewed down 3-fold axis.
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ijms-16-18836-f008: Higher oligomeric structure of ATCase. (A) R-state of Escherichia coli ATCase showing the dodecameric structure with two catalytic trimers (shown in red, magenta and cyan) at the top and bottom, and three regulatory dimers (shown in grey and tints) in the equator; (B) T-state of E. coli ATCase; (C) Structure of Aquifex aeolicus ATCase in complex with dehydroorotase. Two catalytic trimers located at the top and bottom are completely separated by three dehydroorotase dimers in the middle. Left: viewed perpendicular to three-fold axis; right: viewed down 3-fold axis.

Mentions: Most structural studies of ATCase use the E. coli holoenzyme as a model, in which two ATCase catalytic trimers associate with three regulatory dimers to form a heterodimeric dodecameric structure [36]. Because of the restraints imposed by the regulatory subunits, the enzyme remains in the less active T (taut) state when CP binds, but the 80’s loop’s conformation changes bring S80 and K84 into the active site [71]. Subsequent aspartate binding induces conversion of the enzyme from the T state to the more active R (relaxed) state, which involves an elongation of 11 Å along the three-fold molecular axis, a relative rotation of 12° between two catalytic trimers, and a rotation of 15° for each of three regulatory dimers around their two-fold molecular axes (Figure 8A,B). Aspartate binding also induces additional conformational changes in the 80’s and 240’s loops, and relative domain closure of 8° between CP and aspartate domains. As a result, the two substrates are forced close to each other to lower the activation energy for the catalytic reaction.


From Genome to Structure and Back Again: A Family Portrait of the Transcarbamylases.

Shi D, Allewell NM, Tuchman M - Int J Mol Sci (2015)

Higher oligomeric structure of ATCase. (A) R-state of Escherichia coli ATCase showing the dodecameric structure with two catalytic trimers (shown in red, magenta and cyan) at the top and bottom, and three regulatory dimers (shown in grey and tints) in the equator; (B) T-state of E. coli ATCase; (C) Structure of Aquifex aeolicus ATCase in complex with dehydroorotase. Two catalytic trimers located at the top and bottom are completely separated by three dehydroorotase dimers in the middle. Left: viewed perpendicular to three-fold axis; right: viewed down 3-fold axis.
© Copyright Policy
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4581275&req=5

ijms-16-18836-f008: Higher oligomeric structure of ATCase. (A) R-state of Escherichia coli ATCase showing the dodecameric structure with two catalytic trimers (shown in red, magenta and cyan) at the top and bottom, and three regulatory dimers (shown in grey and tints) in the equator; (B) T-state of E. coli ATCase; (C) Structure of Aquifex aeolicus ATCase in complex with dehydroorotase. Two catalytic trimers located at the top and bottom are completely separated by three dehydroorotase dimers in the middle. Left: viewed perpendicular to three-fold axis; right: viewed down 3-fold axis.
Mentions: Most structural studies of ATCase use the E. coli holoenzyme as a model, in which two ATCase catalytic trimers associate with three regulatory dimers to form a heterodimeric dodecameric structure [36]. Because of the restraints imposed by the regulatory subunits, the enzyme remains in the less active T (taut) state when CP binds, but the 80’s loop’s conformation changes bring S80 and K84 into the active site [71]. Subsequent aspartate binding induces conversion of the enzyme from the T state to the more active R (relaxed) state, which involves an elongation of 11 Å along the three-fold molecular axis, a relative rotation of 12° between two catalytic trimers, and a rotation of 15° for each of three regulatory dimers around their two-fold molecular axes (Figure 8A,B). Aspartate binding also induces additional conformational changes in the 80’s and 240’s loops, and relative domain closure of 8° between CP and aspartate domains. As a result, the two substrates are forced close to each other to lower the activation energy for the catalytic reaction.

Bottom Line: 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.

View Article: PubMed Central - PubMed

Affiliation: Center for Genetic Medicine Research, Children's National Medical Center, the George Washington University, Washington, DC 20010, USA. dshi@childrensnational.org.

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.

No MeSH data available.


Related in: MedlinePlus