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194  structures 6767  species 7  interactions 23031  sequences 179  architectures

Family: CPSase_L_D2 (PF02786)

Summary: Carbamoyl-phosphate synthase L chain, ATP binding domain

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Carbamoyl-phosphate synthase L chain, ATP binding domain Provide feedback

Carbamoyl-phosphate synthase catalyses the ATP-dependent synthesis of carbamyl-phosphate from glutamine or ammonia and bicarbonate. This important enzyme initiates both the urea cycle and the biosynthesis of arginine and/or pyrimidines [2]. The carbamoyl-phosphate synthase (CPS) enzyme in prokaryotes is a heterodimer of a small and large chain. The small chain promotes the hydrolysis of glutamine to ammonia, which is used by the large chain to synthesise carbamoyl phosphate. See PF00988. The small chain has a GATase domain in the carboxyl terminus. See PF00117. The ATP binding domain (this one) has an ATP-grasp fold.

Literature references

  1. Waldrop GL, Rayment I, Holden HM; , Biochemistry 1994;33:10249-10256.: Three-dimensional structure of the biotin carboxylase subunit. of acetyl-CoA carboxylase. PUBMED:7915138 EPMC:7915138

  2. Simmer JP, Kelly RE, Rinker AG Jr, Scully JL, Evans DR; , Biol Chem 1990;265:10395-10402.: Mammalian carbamyl phosphate synthetase (CPS). DNA sequence and evolution of the CPS domain of the Syrian hamster multifunctional protein CAD. PUBMED:1972379 EPMC:1972379

  3. Thoden JB, Raushel FM, Benning MM, Rayment I, Holden HM; , Acta Crystallogr D Biol Crystallogr 1999;55:8-24.: The structure of carbamoyl phosphate synthetase determined to 2.1 A resolution. PUBMED:10089390 EPMC:10089390


External database links

This tab holds annotation information from the InterPro database.

InterPro entry IPR005479

Carbamoyl phosphate synthase (CPSase) is a heterodimeric enzyme composed of a small and a large subunit (with the exception of CPSase III, see below). CPSase catalyses the synthesis of carbamoyl phosphate from biocarbonate, ATP and glutamine (EC) or ammonia (EC), and represents the first committed step in pyrimidine and arginine biosynthesis in prokaryotes and eukaryotes, and in the urea cycle in most terrestrial vertebrates [PUBMED:10387030, PUBMED:11212301]. CPSase has three active sites, one in the small subunit and two in the large subunit. The small subunit contains the glutamine binding site and catalyses the hydrolysis of glutamine to glutamate and ammonia. The large subunit has two homologous carboxy phosphate domains, both of which have ATP-binding sites; however, the N-terminal carboxy phosphate domain catalyses the phosphorylation of biocarbonate, while the C-terminal domain catalyses the phosphorylation of the carbamate intermediate [PUBMED:8916922]. The carboxy phosphate domain found duplicated in the large subunit of CPSase is also present as a single copy in the biotin-dependent enzymes acetyl-CoA carboxylase (EC) (ACC), propionyl-CoA carboxylase (EC) (PCCase), pyruvate carboxylase (EC) (PC) and urea carboxylase (EC).

Most prokaryotes carry one form of CPSase that participates in both arginine and pyrimidine biosynthesis, however certain bacteria can have separate forms. The large subunit in bacterial CPSase has four structural domains: the carboxy phosphate domain 1, the oligomerisation domain, the carbamoyl phosphate domain 2 and the allosteric domain [PUBMED:10089390]. CPSase heterodimers from Escherichia coli contain two molecular tunnels: an ammonia tunnel and a carbamate tunnel. These inter-domain tunnels connect the three distinct active sites, and function as conduits for the transport of unstable reaction intermediates (ammonia and carbamate) between successive active sites [PUBMED:12379099]. The catalytic mechanism of CPSase involves the diffusion of carbamate through the interior of the enzyme from the site of synthesis within the N-terminal domain of the large subunit to the site of phosphorylation within the C-terminal domain.

Eukaryotes have two distinct forms of CPSase: a mitochondrial enzyme (CPSase I) that participates in both arginine biosynthesis and the urea cycle; and a cytosolic enzyme (CPSase II) involved in pyrimidine biosynthesis. CPSase II occurs as part of a multi-enzyme complex along with aspartate transcarbamoylase and dihydroorotase; this complex is referred to as the CAD protein [PUBMED:7907330]. The hepatic expression of CPSase is transcriptionally regulated by glucocorticoids and/or cAMP [PUBMED:17397987]. There is a third form of the enzyme, CPSase III, found in fish, which uses glutamine as a nitrogen source instead of ammonia [PUBMED:17451989]. CPSase III is closely related to CPSase I, and is composed of a single polypeptide that may have arisen from gene fusion of the glutaminase and synthetase domains [PUBMED:7932737].

This entry represents the ATP-binding domain found in the large subunit of carbamoyl phosphate synthase, as well as in other proteins, including acetyl-CoA carboxylases and pyruvate carboxylases.

Gene Ontology

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Domain organisation

Below is a listing of the unique domain organisations or architectures in which this domain is found. More...

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Pfam Clan

This family is a member of clan ATP-grasp (CL0179), which has the following description:

The ATP-grasp domain is found in a wide variety of carboxylate-amine/thiol ligases [1]. It is composed of two subdomains, with ATP being bound in the cleft between the two.

The clan contains the following 20 members:

ATP-grasp ATP-grasp_2 ATP-grasp_3 ATP-grasp_4 ATP-grasp_5 ATPgrasp_ST ATPgrasp_Ter ATPgrasp_TupA ATPgrasp_YheCD CP_ATPgrasp_1 CP_ATPgrasp_2 CPSase_L_D2 Dala_Dala_lig_C DUF1297 GARS_A GSH-S_ATP Ins134_P3_kin RimK Synapsin_C TTL

Alignments

We store a range of different sequence alignments for families. As well as the seed alignment from which the family is built, we provide the full alignment, generated by searching the sequence database using the family HMM. We also generate alignments using four representative proteomes (RP) sets, the NCBI sequence database, and our metagenomics sequence database. More...

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We make a range of alignments for each Pfam-A family. You can see a description of each above. You can view these alignments in various ways but please note that some types of alignment are never generated while others may not be available for all families, most commonly because the alignments are too large to handle.

  Seed
(16)
Full
(23031)
Representative proteomes NCBI
(27500)
Meta
(13103)
RP15
(1878)
RP35
(3684)
RP55
(4980)
RP75
(5911)
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Format an alignment

  Seed
(16)
Full
(23031)
Representative proteomes NCBI
(27500)
Meta
(13103)
RP15
(1878)
RP35
(3684)
RP55
(4980)
RP75
(5911)
Alignment:
Format:
Order:
Sequence:
Gaps:
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We make all of our alignments available in Stockholm format. You can download them here as raw, plain text files or as gzip-compressed files.

  Seed
(16)
Full
(23031)
Representative proteomes NCBI
(27500)
Meta
(13103)
RP15
(1878)
RP35
(3684)
RP55
(4980)
RP75
(5911)
Raw Stockholm Download   Download   Download   Download   Download   Download   Download   Download  
Gzipped Download   Download   Download   Download   Download   Download   Download   Download  

You can also download a FASTA format file containing the full-length sequences for all sequences in the full alignment.

External links

MyHits provides a collection of tools to handle multiple sequence alignments. For example, one can refine a seed alignment (sequence addition or removal, re-alignment or manual edition) and then search databases for remote homologs using HMMER3.

HMM logo

HMM logos is one way of visualising profile HMMs. Logos provide a quick overview of the properties of an HMM in a graphical form. You can see a more detailed description of HMM logos and find out how you can interpret them here. More...

Trees

This page displays the phylogenetic tree for this family's seed alignment. We use FastTree to calculate neighbour join trees with a local bootstrap based on 100 resamples (shown next to the tree nodes). FastTree calculates approximately-maximum-likelihood phylogenetic trees from our seed alignment.

Note: You can also download the data file for the tree.

Curation and family details

This section shows the detailed information about the Pfam family. You can see the definitions of many of the terms in this section in the glossary and a fuller explanation of the scoring system that we use in the scores section of the help pages.

Curation View help on the curation process

Seed source: Prosite
Previous IDs: CPSase;
Type: Domain
Author: Finn RD, Griffiths-Jones SR
Number in seed: 16
Number in full: 23031
Average length of the domain: 197.30 aa
Average identity of full alignment: 32 %
Average coverage of the sequence by the domain: 31.79 %

HMM information View help on HMM parameters

HMM build commands:
build method: hmmbuild -o /dev/null HMM SEED
search method: hmmsearch -Z 23193494 -E 1000 --cpu 4 HMM pfamseq
Model details:
Parameter Sequence Domain
Gathering cut-off 19.8 19.8
Trusted cut-off 19.8 19.8
Noise cut-off 19.7 19.7
Model length: 211
Family (HMM) version: 12
Download: download the raw HMM for this family

Species distribution

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Interactions

There are 7 interactions for this family. More...

CPSase_L_D3 Biotin_carb_C CPSase_sm_chain GATase CPSase_L_chain CPSase_L_D2 MGS

Structures

For those sequences which have a structure in the Protein DataBank, we use the mapping between UniProt, PDB and Pfam coordinate systems from the PDBe group, to allow us to map Pfam domains onto UniProt sequences and three-dimensional protein structures. The table below shows the structures on which the CPSase_L_D2 domain has been found. There are 194 instances of this domain found in the PDB. Note that there may be multiple copies of the domain in a single PDB structure, since many structures contain multiple copies of the same protein seqence.

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