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64  structures 6879  species 0  interactions 12923  sequences 139  architectures

# Summary: Shikimate / quinate 5-dehydrogenase

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This is the Wikipedia entry entitled "Shikimate dehydrogenase". More...

# Shikimate dehydrogenase

Shikimate dehydrogenase
Identifiers
EC no.1.1.1.25
CAS no.9026-87-3
Databases
IntEnzIntEnz view
BRENDABRENDA entry
ExPASyNiceZyme view
KEGGKEGG entry
MetaCycmetabolic pathway
PRIAMprofile
PDB structuresRCSB PDB PDBe PDBsum
Gene OntologyAmiGO / QuickGO

In enzymology, a shikimate dehydrogenase (EC 1.1.1.25) is an enzyme that catalyzes the chemical reaction

shikimate + NADP+ ${\displaystyle \rightleftharpoons }$ 3-dehydroshikimate + NADPH + H+

Thus, the two substrates of this enzyme are shikimate and NADP+, whereas its 3 products are 3-dehydroshikimate, NADPH, and H+. This enzyme participates in phenylalanine, tyrosine and tryptophan biosynthesis.

## Function

Shikimate dehydrogenase is an enzyme that catalyzes one step of the shikimate pathway. This pathway is found in bacteria, plants, fungi, algae, and parasites and is responsible for the biosynthesis of aromatic amino acids (phenylalanine, tyrosine, and tryptophan) from the metabolism of carbohydrates. In contrast, animals and humans lack this pathway hence products of this biosynthetic route are essential amino acids that must be obtained through an animal's diet.

There are seven enzymes that play a role in this pathway. Shikimate dehydrogenase (also known as 3-dehydroshikimate dehydrogenase) is the fourth step of the seven step process. This step converts 3-dehydroshikimate to shikimate as well as reduces NADP+ to NADPH.

## Nomenclature

This enzyme belongs to the family of oxidoreductases, specifically those acting on the CH-OH group of donor with NAD+ or NADP+ as acceptor. The systematic name of this enzyme class is shikimate:NADP+ 3-oxidoreductase. Other names in common use include:

• dehydroshikimic reductase,
• shikimate oxidoreductase,
• 5-dehydroshikimate reductase,
• shikimate 5-dehydrogenase,
• 5-dehydroshikimic reductase,
• DHS reductase,
• AroE.

## Reaction

The Shikimate Dehydrogenase Reaction

Shikimate Dehydrogenase catalyzes the reversible NADPH-dependent reaction of 3-dehydroshikimate to shikimate.[1] The enzyme reduces the carbon-oxygen double bond of a carbonyl functional group to a hydroxyl (OH) group, producing the shikimate anion. The reaction is NADPH dependent with NADPH being oxidised to NADP+.

## Structure

### N terminal domain

Shikimate dehydrogenase, N terminal domain
Shikimate dehydrogenase AroE complexed with NADP+
Identifiers
SymbolShikimate_dh_N
PfamPF08501
InterProIPR013708
SCOP21vi2 / SCOPe / SUPFAM

The Shikimate dehydrogenase substrate binding domain found at the N-terminus binds to the substrate, 3-dehydroshikimate.[2] It is considered to be the catalytic domain. It has a structure of six beta strands forming a twisted beta sheet with four alpha helices.[2]

### C terminal domain

Shikimate Dehydrogenase C terminal
Glutamyl-tRNA reductase from methanopyrus kandleri
Identifiers
SymbolShikimate_DH
PfamPF01488
Pfam clanCL0063
InterProIPR006151
SCOP21nyt / SCOPe / SUPFAM

The C-terminal domain binds to NADPH. It has a special structure, a Rossmann fold, whereby six-stranded twisted and parallel beta sheet with loops and alpha helices surrounding the core beta sheet.[2]

The Structure of Shikimate dehydrogenase is characterized by two domains, two alpha helices and two beta sheets with a large cleft separating the domains of the monomer.[3] The enzyme is symmetrical. Shikimate dehydrogenase also has an NADPH binding site that contains a Rossmann fold. This binding site normally contains a glycine P-loop.[1] The domains of the monomer show a fair amount of flexibility suggesting that the enzyme can open in close to bind with the substrate 3-Dehydroshikimate. Hydrophobic interactions occur between the domains and the NADPH binding site.[1] This hydrophobic core and its interactions lock the shape of the enzyme even though the enzyme is a dynamic structure. There is also evidence to support that the structure of the enzyme is conserved, meaning the structure takes sharp turns in order to take up less space.

The cleft in the shikimate dehydrogenase monomer. The green selection is the loops surrounding the cleft, and the red selection shows alpha helices in the background.

## Paralogs

Escherichia coli (E. coli) expresses two different forms of shikimate dehydrogenase, AroE and YdiB. These two forms are paralogs of each other. The two forms of shikimate dehydrogenase have different primary sequences in different organisms but catalyze the same reactions. There is about 25% similarity between the sequences of AroE and YdiB, but their two structures have similar structures with similar folds. YdiB can utilize NAD or NADP as a cofactor and also reacts with quinic acid.[3] They both have high affinity of their ligands as shown by their similar enzyme (Km) values.[3] Both forms of the enzyme are independently regulated.[3]

Shikimate dehydrogenase YdiB with highlighted NADH binding sites. The red color of the surface of the structure shows alpha helices, the yellow shows beta sheets, and the green area shows where there are loops in the enzyme.
The AroE form of shikimate dehydrogenase with highlighted NADP+ binding sites. The red color shows where the alpha helices are, the green shows the loops, and the yellow shows the beta sheets in the structure.

## Applications

The shikimate pathway is a target for herbicides and other non-toxic drugs because the shikimate pathway is not present in humans. Glyphosate, a commonly used herbicide, is an inhibitor of 5-enolpyruvylshikimate 3-phosphate synthase or EPSP synthase, an enzyme in the shikimate pathway. The problem is that this herbicide has been utilized for about 20 years and now some plants have now emerged that are glyphosate-resistant. This has relevance to research on shikimate dehydrogenase because it is important to maintain diversity in the enzyme blocking process in the shikimate pathway and with more research shikimate dehydrogenase could be the next enzyme to be inhibited in the shikimate pathway. In order to design new inhibitors the structures for all the enzymes in the pathway have needed to be elucidated. The presence of two forms of the enzyme complicate the design of potential drugs because one could compensate for the inhibition of the other. Also there the TIGR data base shows that there are 14 species of bacteria with the two forms of shikimate dehydrogenase.[3] This is a problem for drug makers because there are two enzymes that a potential drug would need to inhibit at the same time.[3]

## References

1. ^ a b c Ye S, Von Delft F, Brooun A, Knuth MW, Swanson RV, McRee DE (July 2003). "The crystal structure of shikimate dehydrogenase (AroE) reveals a unique NADPH binding mode". J. Bacteriol. 185 (14): 4144â€“51. doi:10.1128/JB.185.14.4144-4151.2003. PMCÂ 164887. PMIDÂ 12837789.
2. ^ a b c Lee HH (2012). "High-resolution structure of shikimate dehydrogenase from Thermotoga maritima reveals a tightly closed conformation". Mol Cells. 33 (3): 229â€“33. doi:10.1007/s10059-012-2200-x. PMCÂ 3887703. PMIDÂ 22095087.
3. Michel G, Roszak AW, SauvÃ© V, Maclean J, Matte A, Coggins JR, Cygler M, Lapthorn AJ (May 2003). "Structures of shikimate dehydrogenase AroE and its Paralog YdiB. A common structural framework for different activities". J. Biol. Chem. 278 (21): 19463â€“72. doi:10.1074/jbc.M300794200. PMIDÂ 12637497.

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.

# Shikimate / quinate 5-dehydrogenase

This family contains both shikimate and quinate dehydrogenases. Shikimate 5-dehydrogenase catalyses the conversion of shikimate to 5-dehydroshikimate. This reaction is part of the shikimate pathway which is involved in the biosynthesis of aromatic amino acids. Quinate 5-dehydrogenase catalyses the conversion of quinate to 5-dehydroquinate. This reaction is part of the quinate pathway where quinic acid is exploited as a source of carbon in prokaryotes and microbial eukaryotes. Both the shikimate and quinate pathways share two common pathway metabolites 3-dehydroquinate and dehydroshikimate.

## Literature references

1. Hawkins AR, Lamb HK; , Eur J Biochem 1995;232:7-18.: The molecular biology of multidomain proteins. Selected examples. PUBMED:7556173 EPMC:7556173

This tab holds annotation information from the InterPro database.

# InterPro entry IPR006151

This entry represents a domain found in shikimate and quinate dehydrogenases, as well as glutamyl-tRNA reductases.

Shikimate 5-dehydrogenase ( EC ) catalyses the conversion of shikimate to 5-dehydroshikimate [ PUBMED:12906831 , PUBMED:12837789 ]. This reaction is part of the shikimate pathway which is involved in the biosynthesis of aromatic amino acids [ PUBMED:15012217 ]. Quinate 5-dehydrogenase catalyses the conversion of quinate to 5-dehydroquinate. This reaction is part of the quinate pathway where quinic acid is exploited as a source of carbon in prokaryotes and microbial eukaryotes. Both the shikimate and quinate pathways share two common pathway metabolites, 3-dehydroquinate and dehydroshikimate.

Glutamyl-tRNA reductase ( EC ) catalyzes the first step of tetrapyrrole biosynthesis in plants, archaea and most bacteria. The dimeric enzyme has an unusual V-shaped architecture where each monomer consists of three domains linked by a long 'spinal' alpha-helix. The central catalytic domain specifically recognises the glutamate moiety of the substrate [ PUBMED:16228559 ].

# Domain organisation

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

# Pfam Clan

This family is a member of clan NADP_Rossmann (CL0063), which has the following description:

A class of redox enzymes are two domain proteins. One domain, termed the catalytic domain, confers substrate specificity and the precise reaction of the enzyme. The other domain, which is common to this class of redox enzymes, is a Rossmann-fold domain. The Rossmann domain binds nicotinamide adenine dinucleotide (NAD+) and it is this cofactor that reversibly accepts a hydride ion, which is lost or gained by the substrate in the redox reaction. Rossmann domains have an alpha/beta fold, which has a central beta sheet, with approximately five alpha helices found surrounding the beta sheet.The strands forming the beta sheet are found in the following characteristic order 654123. The inter sheet crossover of the stands in the sheet form the NAD+ binding site [1]. In some more distantly relate Rossmann domains the NAD+ cofactor is replaced by the functionally similar cofactor FAD.

The clan contains the following 209 members:

Shikimate_DH

# 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 (reference proteomes) using the family HMM. We also generate alignments using four representative proteomes (RP) sets and the UniProtKB sequence database. More...

## 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
(35)
Full
(12923)
Representative proteomes UniProt
(60667)
RP15
(1813)
RP35
(6297)
RP55
(12781)
RP75
(21931)
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PP/heatmap 1

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

Key: available, not generated, not available.

## Format an alignment

Seed
(35)
Full
(12923)
Representative proteomes UniProt
(60667)
RP15
(1813)
RP35
(6297)
RP55
(12781)
RP75
(21931)
Alignment:
Format:
Order:
Sequence:
Gaps:

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
(35)
Full
(12923)
Representative proteomes UniProt
(60667)
RP15
(1813)
RP35
(6297)
RP55
(12781)
RP75
(21931)

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

# 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.

# 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_336 (release 4.0) Previous IDs: none Type: Family Sequence Ontology: SO:0100021 Author: Bashton M , Bateman A Number in seed: 35 Number in full: 12923 Average length of the domain: 112.80 aa Average identity of full alignment: 24 % Average coverage of the sequence by the domain: 25.96 %

## HMM information

HMM build commands:
build method: hmmbuild -o /dev/null HMM SEED
search method: hmmsearch -Z 61295632 -E 1000 --cpu 4 HMM pfamseq
Model details:
Parameter Sequence Domain
Gathering cut-off 24.3 24.3
Trusted cut-off 24.3 24.3
Noise cut-off 24.2 24.2
Model length: 138
Family (HMM) version: 23

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# 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 Shikimate_DH domain has been found. There are 64 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 sequence.

# AlphaFold Structure Predictions

The list of proteins below match this family and have AlphaFold predicted structures. Click on the protein accession to view the predicted structure.

Protein Predicted structure External Information