Summary: S-adenosyl-L-homocysteine hydrolase

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Wikipedia: S-adenosyl-L-homocysteine hydrolase
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This is the Wikipedia entry entitled "S-adenosyl-L-homocysteine hydrolase". More...

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S-adenosyl-L-homocysteine hydrolase Edit Wikipedia article

S-adenosyl-L-homocysteine hydrolase

Structure of S-adenosylhomocysteine hydrolase from rat liver.^[1]

Identifiers

Symbol

Ad_hcy_hydrolase

1b3r / SUPFAM

Available protein structures:
Pfam	structures / ECOD
PDB	RCSB PDB; PDBe; PDBj
PDBsum	structure summary
PDB	1a7a, 1b3r, 1d4f, 1k0u, 1ky4, 1ky5, 1li4, 1v8b, 1xwf

AdoHcyase NAD-binding domain

d244e mutant s-adenosylhomocysteine hydrolase refined with noncrystallographic restraints

Identifiers

Symbol

AdoHcyase_NAD

Pfam clan

1b3r / SUPFAM

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

S-adenosyl-L-homocysteine hydrolase (EC 3.3.1.1) (AdoHcyase) is an enzyme of the activated methyl cycle, responsible for the reversible hydration of S-adenosyl-L-homocysteine into adenosine and homocysteine.

AdoHcyase is a ubiquitous enzyme which binds and requires NAD⁺ as a cofactor. AdoHcyase is a highly conserved protein^[2] of about 430 to 470 amino acids. The family contains a glycine-rich region in the central part of AdoHcyase; a region thought to be involved in NAD-binding.

AdoHcyase is significantly associated with adenosine deaminase deficiency, which classically manifests in severe combine immunodeficiency (SCID). Accumulated adenosine derivatives, dATPs, irreversibly bind to and inhibit AdoHcyase, promoting the buildup of S-adenosyl-L-homocystine (due to equilibrium constant favors S-adenosyl-L-homocystine), a potent inhibitor of methyl transfer reactions^[3].

This protein may use the morpheein model of allosteric regulation.^[4]

References

^ Hu Y, Komoto J, Huang Y, et al. (June 1999). "Crystal structure of S-adenosylhomocysteine hydrolase from rat liver". Biochemistry. 38 (26): 8323â€“33. doi:10.1021/bi990332k. PMID 10387078.
^ Sganga MW, Aksamit RR, Cantoni GL, Bauer CE (1992). "Mutational and nucleotide sequence analysis of S-adenosyl-L-homocysteine hydrolase from Rhodobacter capsulatus". Proc. Natl. Acad. Sci. U.S.A. 89 (14): 6328â€“6332. Bibcode:1992PNAS...89.6328S. doi:10.1073/pnas.89.14.6328. PMC 49494. PMID 1631127.
^ Hershfield, M S (1979). "In vivo inactivation of erythrocyte S-adenosylhomocysteine hydrolase by 2'-deoxyadenosine in adenosine deaminase-deficient patients". J Clin Invest. 63 (4): 807â€“811. doi:10.1172/JCI109367. PMC 372019. PMID 312296.
^ T. Selwood; E. K. Jaffe. (2011). "Dynamic dissociating homo-oligomers and the control of protein function". Arch. Biochem. Biophys. 519 (2): 131â€“43. doi:10.1016/j.abb.2011.11.020. PMC 3298769. PMID 22182754.

This article incorporates text from the public domain Pfam and InterPro: IPR000043

v t e Enzymes
Activity	Active site Binding site Catalytic triad Oxyanion hole Enzyme promiscuity Catalytically perfect enzyme Coenzyme Cofactor Enzyme catalysis
Regulation	Allosteric regulation Cooperativity Enzyme inhibitor Enzyme activator
Classification	EC number Enzyme superfamily Enzyme family List of enzymes
Kinetics	Enzyme kinetics Eadieâ€“Hofstee diagram Hanesâ€“Woolf plot Lineweaverâ€“Burk plot Michaelisâ€“Menten kinetics
Types	EC1 Oxidoreductases (list) EC2 Transferases (list) EC3 Hydrolases (list) EC4 Lyases (list) EC5 Isomerases (list) EC6 Ligases (list) EC7 Translocases (list)

This page is based on a Wikipedia article. The text is available under the Creative Commons Attribution/Share-Alike License.

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.

S-adenosyl-L-homocysteine hydrolase Provide feedback

No Pfam abstract.

Internal database links

SCOOP:	2-Hacid_dh_C AdoHcyase_NAD AlaDh_PNT_C IlvN NAD_binding_7 Shikimate_DH THF_DHG_CYH_C TrkA_N
Similarity to PfamA using HHSearch:	AdoHcyase_NAD TrkA_N 2-Hacid_dh_C IlvN

External database links

PROSITE:	PDOC00603
SCOP:	1b3r

This tab holds annotation information from the InterPro database.

InterPro entry IPR000043

Adenosylhomocysteinase (S-adenosyl-L-homocysteine hydrolase, EC ) (AdoHcyase) is an enzyme of the activated methyl cycle, responsible for the reversible hydration of S-adenosyl-L-homocysteine into adenosine and homocysteine. This enzyme is ubiquitous, highly conserved, and may play a key role in the regulation of the intracellular concentration of adenosylhomocysteine. AdoHcyase requires NAD+ as a cofactor and contains a central glycine-rich region which is thought to be involved in NAD-binding. Since AdoHyc is a potent inhibitor of S-adenosyl-L-methionine dependent methyltransferases, AdoHycase plays a critical role in the modulation of the activity of various methyltransferases. The enzyme forms homotetramers, with each monomer binding one molecule of NAD+ [ PUBMED:9586999 , PUBMED:16061414 , PUBMED:11325033 , PUBMED:15165742 ].

This family also includes S-adenosylhomocysteine hydrolase-like 1 (Ahcyl1), also known as IRBIT, and S-adenosylhomocysteine hydrolase-like protein 2 (Ahcyl2). Ahcyl1/IRBIT was shown to interact with inositol 1,4,5-trisphosphate receptors (IP3Rs), which function as intracellular Ca(2+) channels, and suppresses IP3 binding of IP3R [ PUBMED:16793548 , PUBMED:16527252 ]. By competing with IP3, it modulates the threshold IP3 concentration required for the activation of the receptor [ PUBMED:16793548 ]. Further studies indicate that Ahcyl1/IRBIT is in fact a multifunctional protein that regulates several ion channels and ion transporters [ PUBMED:24518248 , PUBMED:21152975 ]. Despite its homology to S-adenosylhomocysteine hydrolases, Ahcyl1 has neither enzyme activity nor any effects on the enzyme activity of S-adenosylhomocysteine hydrolase [ PUBMED:12525476 ]. Ahcyl2 lacks binding activity to IP3R [ PUBMED:19220705 ]. Ahcyl2 upregulates NBCe1-B, which plays an important role in intracellular pH regulation [ PUBMED:27382360 ].

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 Form_Glyc_dh (CL0325), which has the following description:

This superfamily includes the catalytic domain of a variety of dehydrogenase enzymes. The domain has a flavodoxin-like fold and contains an inserted Rossman fold NAD-binding domain.

The clan contains the following 4 members:

2-Hacid_dh AdoHcyase AlaDh_PNT_N DpaA_N

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...

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
UniProt: alignment generated by searching the UniProtKB sequence database using the family HMM

Viewing

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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.

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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 (144)	Full (14475)	Representative proteomes				UniProt (53982)
	Seed (144)	Full (14475)	RP15 (2234)	RP35 (6595)	RP55 (13541)	RP75 (21155)	UniProt (53982)
Jalview	View	View	View	View	View	View	View
HTML	View
PP/heatmap	₁

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

Key: available, not generated, — not available.

Format an alignment

	Seed (144)	Full (14475)	Representative proteomes				UniProt (53982)
	Seed (144)	Full (14475)	RP15 (2234)	RP35 (6595)	RP55 (13541)	RP75 (21155)	UniProt (53982)
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 (144)	Full (14475)	Representative proteomes				UniProt (53982)
	Seed (144)	Full (14475)	RP15 (2234)	RP35 (6595)	RP55 (13541)	RP75 (21155)	UniProt (53982)
Raw Stockholm	Download	Download	Download	Download	Download	Download	Download
Gzipped	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.

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_157 (release 2.1)

Previous IDs:

none

Type:

Domain

Sequence Ontology:

SO:0000417

Author:

Finn RD

Number in seed:

144

Number in full:

14475

Average length of the domain:

275.60 aa

Average identity of full alignment:

36 %

Average coverage of the sequence by the domain:

93.84 %

HMM information

HMM build commands:

build method: hmmbuild -o /dev/null --hand HMM SEED

search method: hmmsearch -Z 57096847 -E 1000 --cpu 4 HMM pfamseq

Model details:

Parameter	Sequence	Domain
Gathering cut-off	25.0	25.0
Trusted cut-off	25.3	25.0
Noise cut-off	24.5	24.9

Model length:

299

Family (HMM) version:

19

Download:

download the raw HMM for this family

Species distribution

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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:

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family
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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.

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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.

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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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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 AdoHcyase domain has been found. There are 320 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.

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v t e Hydrolases: ether bond (EC 3.3)
3.3.1	Adenosylhomocysteinase
3.3.2	Epoxide hydrolase Leukotriene-A4 hydrolase

Family: AdoHcyase (PF05221)

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