Summary: Pterin binding enzyme

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Wikipedia: Dihydropteroate synthase
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Dihydropteroate synthase Edit Wikipedia article

Dihydropteroate synthase

Tetrahydrofolate synthesis pathway

Identifiers

Databases

PDB structures

AmiGO / EGO

Search
PMC	articles
PubMed	articles
NCBI	proteins

Pterin binding enzyme

Identifiers

Symbol

Pterin_bind

Available protein structures:
Pfam	structures
PDB	RCSB PDB; PDBe
PDBsum	structure summary

Dihydropteroate synthase is an enzyme classified under EC 2.5.1.15. It produces dihydropteroate in bacteria, but it is not expressed in most eukaryotes including humans. This makes it a useful target for sulfonamide antibiotics, which compete with the PABA precursor.

(2-amino-4-hydroxy-7,8-dihydropteridin-6-yl)methyl diphosphate + 4-aminobenzoate (PABA) $\rightleftharpoons$ diphosphate + dihydropteroate.

All organisms require reduced folate cofactors for the synthesis of a variety of metabolites. Most microorganisms must synthesize folate de novo because they lack the active transport system of higher vertebrate cells that allows these organisms to use dietary folates. Proteins containing this domain include dihydropteroate synthase (EC 2.5.1.15) as well as a group of methyltransferase enzymes including methyltetrahydrofolate, corrinoid iron-sulphur protein methyltransferase (MeTr) Q46389 that catalyses a key step in the Wood-Ljungdahl pathway of carbon dioxide fixation.

Dihydropteroate synthase (EC 2.5.1.15) (DHPS) catalyses the condensation of 6-hydroxymethyl-7,8-dihydropteridine pyrophosphate to para-aminobenzoic acid to form 7,8-dihydropteroate. This is the second step in the three-step pathway leading from 6-hydroxymethyl-7,8-dihydropterin to 7,8-dihydrofolate. DHPS is the target of sulphonamides, which are substrate analogues that compete with para-aminobenzoic acid. Bacterial DHPS (gene sul or folP)^[1] is a protein of about 275 to 315 amino acid residues that is either chromosomally encoded or found on various antibiotic resistance plasmids. In the lower eukaryote Pneumocystis carinii, DHPS is the C-terminal domain of a multifunctional folate synthesis enzyme (gene fas).^[2]

References[edit]

^ Crawford IP, Slock J, Stahly DP, Six EW, Han CY (1990). "An apparent Bacillus subtilis folic acid biosynthetic operon containing pab, an amphibolic trpG gene, a third gene required for synthesis of para-aminobenzoic acid, and the dihydropteroate synthase gene". J. Bacteriol. 172 (12): 7211â7226. PMC 210846. PMID 2123867.
^ Volpe F, Dyer M, Scaife JG, Darby G, Stammers DK, Delves CJ (1992). "The multifunctional folic acid synthesis fas gene of Pneumocystis carinii appears to encode dihydropteroate synthase and hydroxymethyldihydropterin pyrophosphokinase". Gene 112 (2): 213â218. doi:10.1016/0378-1119(92)90378-3. PMID 1313386.

External links[edit]

Dihydropteroate synthetase at the US National Library of Medicine Medical Subject Headings (MeSH)

Transferases: alkyl and aryl (EC 2.5)

2.5.1

B
enzm
1.1
- 2
- 3
- 4
- 5
- 6
- 7
- 8
- 10
- 11
- 13
- 14
- 15-18
2.1
- 2
- 3
- 4
- 5
- 6
- 7
  - 2.7.10
  - 11-12
- 8
3.1
- - 3.1.3.48
- 2
- 3
- 4
  - 3.4.21
  - 22
  - 23
  - 24
- 5
- 6
- 7
4.1
- 2
- 3
- 4
- 5
- 6
5.1
- 2
- 3
- 4
- 99
6.1-3
- 4
- 5-6

Metabolism of vitamins, coenzymes, and cofactors

Fat soluble vitamins

Vitamin A	Retinol binding protein

Vitamin E	Alpha-tocopherol transfer protein

Vitamin D	liver (Sterol 27-hydroxylase or CYP27A1) Â· renal (25-Hydroxyvitamin D₃ 1-alpha-hydroxylase or CYP27B1) Â· degradation (1,25-Dihydroxyvitamin D₃ 24-hydroxylase or CYP24A1)

Vitamin K	Vitamin K epoxide reductase

Water soluble vitamins

Thiamine (B₁)	Thiamine diphosphokinase

Niacin (B₃)	Indoleamine 2,3-dioxygenase Â· Formamidase

Pantothenic acid (B₅)	Pantothenate kinase

Folic acid (B₉)	Dihydropteroate synthase Â· Dihydrofolate reductase Â· Serine hydroxymethyltransferase Methylenetetrahydrofolate reductase

Vitamin B₁₂	MMAA Â· MMAB Â· MMACHC Â· MMADHC

Vitamin C	L-gulonolactone oxidase

Riboflavin (B₂)	Riboflavin kinase

Nonvitamin cofactors

Tetrahydrobiopterin	GTP cyclohydrolase I Â· 6-pyruvoyltetrahydropterin synthase Â· Sepiapterin reductase PCBD1 Â· PTS Â· QDPR

Molybdenum cofactor	MOCS1 Â· MOCS2 Â· MOCS3 Â· GPHN

M: NUT

cof, enz, met

noco, nuvi, sysi/epon, met

drug (A8/11/12)

This article incorporates text from the public domain Pfam and InterPro IPR000489

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This tab holds the annotation information that is stored in the Pfam database. As we move to using Wikipedia as our main source of annotation, the contents of this tab will be gradually replaced by the Wikipedia tab.

Pterin binding enzyme Provide feedback

This family includes a variety of pterin binding enzymes that all adopt a TIM barrel fold. The family includes dihydropteroate synthase EC:2.5.1.15 as well as a group methyltransferase enzymes including methyltetrahydrofolate, corrinoid iron-sulfur protein methyltransferase (MeTr) Q46389 that catalyses a key step in the Wood-Ljungdahl pathway of carbon dioxide fixation. It transfers the N5-methyl group from methyltetrahydrofolate (CH3-H4folate) to a cob(I)amide centre in another protein, the corrinoid iron-sulfur protein. MeTr is a member of a family of proteins that includes methionine synthase and methanogenic enzymes that activate the methyl group of methyltetra-hydromethano(or -sarcino)pterin [2].

Literature references

Achari A, Somers DO, Champness JN, Bryant PK, Rosemond J, Stammers DK , Nat Struct Biol 1997;4:490-497.: Crystal structure of the anti-bacterial sulfonamide drug target dihydropteroate synthase. PUBMED:9187658 EPMC:9187658
Doukov T, Seravalli J, Stezowski JJ, Ragsdale SW; , Structure Fold Des 2000;8:817-830.: Crystal structure of a methyltetrahydrofolate- and corrinoid-dependent methyltransferase. PUBMED:10997901 EPMC:10997901

External database links

HOMSTRAD:	DHPS
PANDIT:	PF00809
PROSITE:	PDOC00630
Pseudofam:	PF00809
SCOP:	1ajz
SYSTERS:	Pterin_bind

This tab holds annotation information from the InterPro database.

InterPro entry IPR000489

The ~250-residue pterin-binding domain has been shown to adopt a (beta/alpha)8 barrel fold, which has the overall shape of a distorted cylinder. It has eight alpha-helices stacked around the outside of an inner cylinder of parallel beta-strands. The pterin ring binds at the bottom of the (beta/alpha;)8 barrel in a polar cup-like region that is relatively solvent exposed and fairly negatively charged. The pterin ring is partially buried within the (beta/alpha)8 barrel. The pterin binding residues are highly conserved and include aspartate and asparagine residues located at the C terminus of the beta-strands of the barrel, which are predicted to form hydrogen bonds with the nitrogen and oxygen atoms of the pterin ring [PUBMED:10997901, PUBMED:9187658, PUBMED:14752199].

Some proteins known to contain a pterin-binding domain are listed below:

Prokaryotic and eukaryotic B12-dependent methionine synthase (MetH) (EC), a large, modular protein that catalyzes the transfer of a methyl group from methyltetrahydrofolate (CH3-H4folate) to Hcy to form methionine, using cobalamin as an intermediate methyl carrier.
Prokaryotic and eukaryotic dihydropteroate synthase (DHPS) (EC). It catalyzes the condensation of para-aminobenzoic acid (pABA) with 7,8- dihydropterin-pyrophosphate (DHPPP), eliminating pyrophosphate to form 7,8- dihydropteroate which is subsequently converted to tetrahydrofolate.
Moorella thermoacetica 5-methyltetrahydrofolate corrinoid/iron sulphur protein methyltransferase (MeTr). It transfers the N5-methyl group from CH3-H4folate to a cob(I)amide centre in another protein, the corrinoid iron sulphur protein.

Gene Ontology

The mapping between Pfam and Gene Ontology is provided by InterPro. If you use this data please cite InterPro.

Biological process

pteridine-containing compound metabolic process (GO:0042558)

Domain organisation

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

Loading domain graphics...

Pfam Clan

This family is a member of clan TIM_barrel (CL0036), which contains the following 57 members:

Ala_racemase_N ALAD Aldolase AP_endonuc_2 BtpA CdhD CutC DAHP_synth_1 DAHP_synth_2 DeoC DHDPS DHO_dh DHquinase_I DUF1341 DUF2090 DUF556 DUF561 DUF692 DUF993 Dus F_bP_aldolase FMN_dh G3P_antiterm Glu_syn_central Glu_synthase His_biosynth HMGL-like IGPS IMPDH iPGM_N MtrH NanE NAPRTase NeuB NMO OMPdecase Orn_Arg_deC_N Oxidored_FMN PcrB PdxJ PhosphMutase PRAI Pterin_bind QRPTase_C Racemase_4 RhaA Ribul_P_3_epim SOR_SNZ Tagatose_6_P_K ThiG TIM TIM-br_sig_trns TMP-TENI Transaldolase Trp_syntA UvdE UxuA

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...

There are various ways to view or download the sequence alignments that we store. We provide several sequence viewers and a plain-text Stockholm-format file for download.

Alignment types

We make a range of alignments for each Pfam-A family:

seed: the curated alignment from which the HMM for the family is built
full: the alignment generated by searching the sequence database using the HMM
RP15/RP35/RP55/RP75: Representative Proteomes (RPs) at 15%, 35%, 55% and 75% co-membership thresholds
NCBI: alignment generated by searching the NCBI sequence database using the family HMM
meta: alignment generated by searching the metagenomics sequence database using the family HMM

Viewing

You can see the alignments as HTML or in three different sequence viewers:

jalview: a Java applet developed at the University of Dundee. You will need Java installed before running jalview
HTML: an HTML page showing the whole alignment.Please note: full Pfam alignments can be very large. These HTML views are extremely large and often cause problems for browsers. Please use either jalview or the Pfam viewer if you have trouble viewing the HTML version
PP/Heatmap: an HTML-based representation of the alignment, coloured according to the posterior-probability (PP) values from the HMM. As for the standard HTML view, heatmap alignments can also be very large and slow to render.
Pfam viewer: an HTML-based viewer that uses DAS to retrieve alignment fragments on request

Reformatting

You can download (or view in your browser) a text representation of a Pfam alignment in various formats:

Selex
Stockholm
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You can also change the order in which sequences are listed in the alignment, change how insertions are represented, alter the characters that are used to represent gaps in sequences and, finally, choose whether to download the alignment or to view it in your browser directly.

Downloading

You may find that large alignments cause problems for the viewers and the reformatting tool, so we also provide all alignments in Stockholm format. You can download either the plain text alignment, or a gzipped version of it.

View options

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 (42)	Full (8265)	Representative proteomes				NCBI (6541)	Meta (3687)
	Seed (42)	Full (8265)	RP15 (718)	RP35 (1410)	RP55 (1818)	RP75 (2104)	NCBI (6541)	Meta (3687)
Jalview	View	View	View	View	View	View	View	View
HTML	View		View	View	View	View
PP/heatmap	₁		View	View	View	View
Pfam viewer	View	View

¹Cannot generate PP/Heatmap alignments for seeds; no PP data available

Key: available, not generated, — not available.

Format an alignment

	Seed (42)	Full (8265)	Representative proteomes				NCBI (6541)	Meta (3687)
	Seed (42)	Full (8265)	RP15 (718)	RP35 (1410)	RP55 (1818)	RP75 (2104)	NCBI (6541)	Meta (3687)
Alignment:
Format:
Order:	Tree Alphabetical
Sequence:	Inserts lower case All upper case
Gaps:
Download/view:	Download View

Download options

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 (42)	Full (8265)	Representative proteomes				NCBI (6541)	Meta (3687)
	Seed (42)	Full (8265)	RP15 (718)	RP35 (1410)	RP55 (1818)	RP75 (2104)	NCBI (6541)	Meta (3687)
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

Seed source:

Pfam-B_1411 (release 2.1) and Pfam-B_3423 (release 6.6)

Previous IDs:

DHPS;

Type:

Domain

Author:

Bateman A

Number in seed:

42

Number in full:

8265

Average length of the domain:

202.90 aa

Average identity of full alignment:

28 %

Average coverage of the sequence by the domain:

37.28 %

HMM information

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	25.5	25.5
Trusted cut-off	25.7	25.5
Noise cut-off	25.4	25.4

Model length:

210

Family (HMM) version:

17

Download:

download the raw HMM for this family

Species distribution

Sunburst
Tree

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This visualisation provides a simple graphical representation of the distribution of this family across species. You can find the original interactive tree in the adjacent tab. More...

This chart is a modified "sunburst" visualisation of the species tree for this family. It shows each node in the tree as a separate arc, arranged radially with the superkingdoms at the centre and the species arrayed around the outermost ring.

How the sunburst is generated

The tree is built by considering the taxonomic lineage of each sequence that has a match to this family. For each node in the resulting tree, we draw an arc in the sunburst. The radius of the arc, its distance from the root node at the centre of the sunburst, shows the taxonomic level ("superkingdom", "kingdom", etc). The length of the arc represents either the number of sequences represented at a given level, or the number of species that are found beneath the node in the tree. The weighting scheme can be changed using the sunburst controls.

In order to reduce the complexity of the representation, we reduce the number of taxonomic levels that we show. We consider only the following eight major taxonomic levels:

superkingdom
kingdom
phylum
class
order
family
genus
species

Colouring and labels

Segments of the tree are coloured approximately according to their superkingdom. For example, archeal branches are coloured with shades of orange, eukaryotes in shades of purple, etc. The colour assignments are shown under the sunburst controls. Where space allows, the name of the taxonomic level will be written on the arc itself.

As you move your mouse across the sunburst, the current node will be highlighted. In the top section of the controls panel we show a summary of the lineage of the currently highlighed node. If you pause over an arc, a tooltip will be shown, giving the name of the taxonomic level in the title and a summary of the number of sequences and species below that node in the tree.

Anomalies in the taxonomy tree

There are some situations that the sunburst tree cannot easily handle and for which we have work-arounds in place.

Missing taxonomic levels

Some species in the taxonomic tree may not have one or more of the main eight levels that we display. For example, Bos taurus is not assigned an order in the NCBI taxonomic tree. In such cases we mark the omitted level with, for example, "No order", in both the tooltip and the lineage summary.

Unmapped species names

The tree is built by looking at each sequence in the full alignment for the family. We take the name of the species given by UniProt and try to map that to the full taxonomic tree from NCBI. In some cases, the name chosen by UniProt does not map to any node in the NCBI tree, perhaps because the chosen name is listed as a synonym or a misspelling in the NCBI taxonomy.

So that these nodes are not simply omitted from the sunburst tree, we group them together in a separate branch (or segment of the sunburst tree). Since we cannot determine the lineage for these unmapped species, we show all levels between the superkingdom and the species as "uncategorised".

Sub-species

Since we reduce the species tree to only the eight main taxonomic levels, sequences that are mapped to the sub-species level in the tree would not normally be shown. Rather than leave out these species, we map them instead to their parent species. So, for example, for sequences belonging to one of the Vibrio cholerae sub-species in the NCBI taxonomy, we show them instead as belonging to the species Vibrio cholerae.

Too many species/sequences

For large species trees, you may see blank regions in the outer layers of the sunburst. These occur when there are large numbers of arcs to be drawn in a small space. If an arc is less than approximately one pixel wide, it will not be drawn and the space will be left blank. You may still be able to get some information about the species in that region by moving your mouse across the area, but since each arc will be very small, it will be difficult to accurately locate a particular species.

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Species trees

We show the species tree in one of two ways. For smaller trees we try to show an interactive representation, which allows you to select specific nodes in the tree and view them as an alignment or as a set of Pfam domain graphics.

Unfortunately we have found that there are problems viewing the interactive tree when the it becomes larger than a certain limit. Furthermore, we have found that Internet Explorer can become unresponsive when viewing some trees, regardless of their size. We therefore show a text representation of the species tree when the size is above a certain limit or if you are using Internet Explorer to view the site.

If you are using IE you can still load the interactive tree by clicking the "Generate interactive tree" button, but please be aware of the potential problems that the interactive species tree can cause.

Interactive tree

For all of the domain matches in a full alignment, we count the number that are found on all sequences in the alignment. This total is shown in the purple box.

We also count the number of unique sequences on which each domain is found, which is shown in green. Note that a domain may appear multiple times on the same sequence, leading to the difference between these two numbers.

Finally, we group sequences from the same organism according to the NCBI code that is assigned by UniProt, allowing us to count the number of distinct sequences on which the domain is found. This value is shown in the pink boxes.

We use the NCBI species tree to group organisms according to their taxonomy and this forms the structure of the displayed tree. Note that in some cases the trees are too large (have too many nodes) to allow us to build an interactive tree, but in most cases you can still view the tree in a plain text, non-interactive representation. Those species which are represented in the seed alignment for this domain are highlighted.

You can use the tree controls to manipulate how the interactive tree is displayed:

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highlight species that are represented in the seed alignment
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Interactions

There are 3 interactions for this family. More...

S-methyl_trans Pterin_bind HPPK

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 Pterin_bind domain has been found. There are 134 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.

Loading structure mapping...

Archea	Eukaryota
Bacteria	Other sequences
Viruses	Unclassified
Viroids	Unclassified sequence

Family: Pterin_bind (PF00809)

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Summary: Pterin binding enzyme

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Dihydropteroate synthase Edit Wikipedia article

References[edit]

External links[edit]

Pterin binding enzyme Provide feedback

Literature references

External database links

InterPro entry IPR000489

Gene Ontology

Domain organisation

Pfam Clan

Alignments

Alignment types

Viewing

Reformatting

Downloading

View options

Format an alignment

Download options

External links

HMM logo

Trees

Curation and family details

Curation

HMM information

Species distribution

Sunburst controls

Weight segments by...

Change the size of the sunburst

Colour assignments

Selections

Currently selected:

How the sunburst is generated

Colouring and labels

Anomalies in the taxonomy tree

Missing taxonomic levels

Unmapped species names

Sub-species

Too many species/sequences

Tree controls

Annotation

Download tree

Selected sequences

Species trees

Interactive tree

Interactions

Structures