Summary: Thiolase, N-terminal domain

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Thiolase Edit Wikipedia article

Not to be confused with Acyl-CoA:cholesterol acyltransferase or Acetyl-CoA C-acyltransferase.

Thiolase, N-terminal domain

Identifiers

Symbol

Thiolase_N

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

Thiolase, C-terminal domain

Identifiers

Symbol

Thiolase_C

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

Mevalonate pathway

Thiolases, also known as acetyl-coenzyme A acetyltransferases (ACAT), are enzymes which convert two units of acetyl-CoA to acetoacetyl CoA in the mevalonate pathway.

Thiolases are ubiquitous enzymes that have key roles in many vital biochemical pathways, including the beta oxidation pathway of fatty acid degradation and various biosynthetic pathways.^[1] Members of the thiolase family can be divided into two broad categories: degradative thiolases (EC 2.3.1.16) and biosynthetic thiolases (EC 2.3.1.9). These two different types of thiolase are found both in eukaryotes and in prokaryotes: acetoacetyl-CoA thiolase (EC:2.3.1.9) and 3-ketoacyl-CoA thiolase (EC:2.3.1.16). 3-ketoacyl-CoA thiolase (also called thiolase I) has a broad chain-length specificity for its substrates and is involved in degradative pathways such as fatty acid beta-oxidation. Acetoacetyl-CoA thiolase (also called thiolase II) is specific for the thiolysis of acetoacetyl-CoA and involved in biosynthetic pathways such as poly beta-hydroxybutyric acid synthesis or steroid biogenesis.

The formation of a carbon–carbon bond is a key step in the biosynthetic pathways by which fatty acids and polyketide are made. The thiolase superfamily enzymes catalyse the carbon–carbon-bond formation via a thioester-dependent Claisen condensation^[2] reaction mechanism.^[3]

Function

Thiolases are a family of evolutionarily related enzymes. Two different types of thiolase^[4]^[5]^[6] are found both in eukaryotes and in prokaryotes: acetoacetyl-CoA thiolase (EC 2.3.1.9) and 3-ketoacyl-CoA thiolase (EC 2.3.1.16). 3-ketoacyl-CoA thiolase (also called thiolase I) has a broad chain-length specificity for its substrates and is involved in degradative pathways such as fatty acid beta-oxidation. Acetoacetyl-CoA thiolase (also called thiolase II) is specific for the thiolysis of acetoacetyl-CoA and involved in biosynthetic pathways such as poly beta-hydroxybutyrate synthesis or steroid biogenesis.

In eukaryotes, there are two forms of 3-ketoacyl-CoA thiolase: one located in the mitochondrion and the other in peroxisomes.

There are two conserved cysteine residues important for thiolase activity. The first located in the N-terminal section of the enzymes is involved in the formation of an acyl-enzyme intermediate; the second located at the C-terminal extremity is the active site base involved in deprotonation in the condensation reaction.

Isozymes

EC number	Name	Alternate name	Isozymes	Subcellular distribution
EC 2.3.1.9	Acetyl-CoA C-acetyltransferase	thiolase II; Acetoacetyl-CoA thiolase	ACAT1	mitochondrial
EC 2.3.1.9	Acetyl-CoA C-acetyltransferase	thiolase II; Acetoacetyl-CoA thiolase	ACAT2	cytosolic
EC 2.3.1.16	Acetyl-CoA C-acyltransferase	thiolase I; 3-Ketoacyl-CoA thiolase; β-Ketothiolase	ACAA1	peroxisomal
			ACAA2	mitochondrial
			HADHB	mitochondrial
EC 2.3.1.154	Propionyl-CoA C2-trimethyltridecanoyltransferase	3-Oxopristanoyl-CoA thiolase
EC 2.3.1.174	3-Oxoadipyl-CoA thiolase	β-Ketoadipyl-CoA thiolase
EC 2.3.1.176	Propanoyl-CoA C-acyltransferase	Peroxisomal thiolase 2	SCP2	peroxisomal/cytosolic

Mammalian nonspecific lipid-transfer protein (nsL-TP) (also known as sterol carrier protein 2) is a protein which seems to exist in two different forms: a 14 Kd protein (SCP-2) and a larger 58 Kd protein (SCP-x). The former is found in the cytoplasm or the mitochondria and is involved in lipid transport; the latter is found in peroxisomes. The C-terminal part of SCP-x is identical to SCP-2 while the N-terminal portion is evolutionary related to thiolases.^[6]

Mechanism

Reaction catalyzed by thiolase

Thioesters are more reactive than oxygen esters and are common intermediates in fatty-acid metabolism.^[7] These thioesters are made by conjugating the fatty acid with the free SH group of the pantetheine moiety of either coenzyme A (CoA) or acyl carrier protein (ACP).

All thiolases, whether they are biosynthetic or degradative in vivo, preferentially catalyze the degradation of 3-ketoacyl-CoA to form acetyl-CoA and a shortened acyl-CoA species, but are also capable of catalyzing the reverse Claisen condensation reaction. It is well established from studies on the biosynthetic thiolase from Z. ramigera that the thiolase reaction occurs in two steps and follows ping-pong kinetics.^[8] In the first step of both the degradative and biosynthetic reactions, the nucleophilic Cys89 (or its equivalent) attacks the acyl-CoA (or 3-ketoacyl-CoA) substrate,leading to the formation of a covalent acyl-CoA intermediate.^[9] In the second step, the addition of CoA (in the degradative reaction) or acetyl-CoA (in the biosynthetic reaction) to the acyl–enzyme intermediate triggers the release of the product from the enzyme.^[10]

Thiolase Mechanism. The two-step, ping-pong mechanism for the thiolase reaction. Red arrows indicate the biosynthetic reaction; Black arrows trace the degradative reaction. In both directions, the reaction is initiated by the nucleophilic attack of Cys89 on the substrate to form a covalent acetyl–enzyme intermediate. Cys89 is activated for nucleophilic attack by His348, which abstracts the sulfide proton of Cys89. In the second step of both the biosynthetic and degradative reactions, the substrate nucleophilically attacks the acetyl–enzyme intermediate to yield the final product and free enzyme. This nucleophilic attack is activated by Cys378, which abstracts a proton from the substrate.

Structure

Most enzyme of the thiolase super family are dimers. However, monomers have not been observed. Tetrameters are observed only in the thiolase subfamily and, in these cases, the dimers have dimerized to become tetramers. The crystal structure of the tetrameric biosynthetic thiolase from Zoogloea ramigera has been determined at 2.0 Å resolution. The structure contains a striking and novel ‘cage-like’ tetramerization motif, which allows for some hinge motion of the two tight dimers with respect to each other. The enzyme tetramer is acetylated at Cys89 and has a CoA molecule bound in each of its active-site pockets.^[11]

Biological function

In eukaryotic cells, especially in mammalian cells, thiolases exhibit diversity in intracellular localization related to their metabolic functions as well as in substrate specificity. For example, they contribute to fatty-acid β-oxidation in peroxisomes and mitochondria, ketone body metabolism in mitochondria,^[12] and the early steps of mevalonate pathway in peroxisomes and cytoplasm.^[13] In addition to biochemical investigations, analyses of genetic disorders have made clear the basis of their functions.^[14] Genetic studies have also started to disclose the physiological functions of thiolases in the yeast Saccharomyces cerevisiae.^[15] Thiolase is of central importance in key enzymatic pathways such as fatty-acid, steroid and polyketide synthesis. The detailed understanding of its structural biology is of great medical relevance, for example, for a better understanding of the diseases caused by genetic deficiencies of these enzymes and for the development of new antibiotics.^[16] Harnessing the complicated catalytic versatility of the polyketide synthases for the synthesis of biologically and medically relevant natural products is also an important future perspective of the studies of the enzymes of this superfamily.^[17]

Disease relevance

Mitochondrial acetoacetyl-CoA thiolase deficiency, known earlier as β-ketothiolase deficiency,^[18] is an inborn error of metabolism involving isoleucine catabolism and ketone body metabolism. The major clinical manifestations of this disorder are intermittent ketoacidosis but the long-term clinical consequences, apparently benign, are not well documented. Mitochondrial acetoacetyl-CoA thiolase deficiency is easily diagnosed by urinary organic acid analysis and can be confirmed by enzymatic analysis of cultured skin fibroblasts or blood leukocytes.^[19]

β-Ketothiolase Deficiency has a variable presentation. Most affected patients present between 5 and 24 months of age with symptoms of severe ketoacidosis. Symptoms can be initiated by a dietary protein load, infection or fever. Symptoms progress from vomiting to dehydration and ketoacidosis.^[20] Neutropenia and thrombocytopenia may be present, as can moderate hyperammonemia. Blood glucose is typically normal, but can be low or high in acute episodes.^[21] Developmental delay may occur, even before the first acute episode, and bilateral striatal necrosis of the basal ganglia has been seen on brain MRI.

References

^ Thompson S, Mayerl F, Peoples OP, Masamune S, Sinskey AJ, Walsh CT (July 1989). "Mechanistic studies on beta-ketoacyl thiolase from Zoogloea ramigera: identification of the active-site nucleophile as Cys89, its mutation to Ser89, and kinetic and thermodynamic characterization of wild-type and mutant enzymes". Biochemistry. 28 (14): 5735–42. doi:10.1021/bi00440a006. PMID 2775734.
^ Heath RJ, Rock CO (October 2002). "The Claisen condensation in biology". Nat Prod Rep. 19 (5): 581–96. doi:10.1039/b110221b. PMID 12430724.
^ Haapalainen AM, Meriläinen G, Wierenga RK (January 2006). "The thiolase superfamily: condensing enzymes with diverse reaction specificities". Trends Biochem. Sci. 31 (1): 64–71. doi:10.1016/j.tibs.2005.11.011. PMID 16356722.
^ Baker ME, Billheimer JT, Strauss JF (November 1991). "Similarity between the amino-terminal portion of mammalian 58-kD sterol carrier protein (SCPx) and Escherichia coli acetyl-CoA acyltransferase: evidence for a gene fusion in SCPx". DNA Cell Biol. 10 (9): 695–8. doi:10.1089/dna.1991.10.695. PMID 1755959.
^ Yang SY, Yang XY, Healy-Louie G, Schulz H, Elzinga M (June 1990). "Nucleotide sequence of the fadA gene. Primary structure of 3-ketoacyl-coenzyme A thiolase from Escherichia coli and the structural organization of the fadAB operon". J. Biol. Chem. 265 (18): 10424–9. PMID 2191949.
^ ^a ^b Igual JC, González-Bosch C, Dopazo J, Pérez-Ortín JE (August 1992). "Phylogenetic analysis of the thiolase family. Implications for the evolutionary origin of peroxisomes". J. Mol. Evol. 35 (2): 147–55. doi:10.1007/BF00183226. PMID 1354266.
^ Enzymatic reaction mechanisms. San Francisco: W. H. Freeman. 1979. ISBN 0-7167-0070-0.
^ Masamune, Satoru; Walsh, Christopher T.; Gamboni, Remo; Thompson, Stuart; Davis, Jeffrey T.; Williams, Simon F.; Peoples, Oliver P.; Sinskey, Anthony J.; Walsh, Christopher T. (1989). "Bio-Claisen condensation catalyzed by thiolase from Zoogloea ramigera. Active site cysteine residues". J. Am. Chem. Soc. 111 (5): 1879, 1991. doi:10.1021/ja00187a053.
^ Gilbert HF, Lennox BJ, Mossman CD, Carle WC (July 1981). "The relation of acyl transfer to the overall reaction of thiolase I from porcine heart". J. Biol. Chem. 256 (14): 7371–7. PMID 6114098.
^ Mathieu M, Modis Y, Zeelen JP, et al. (October 1997). "The 1.8 A crystal structure of the dimeric peroxisomal 3-ketoacyl-CoA thiolase of Saccharomyces cerevisiae: implications for substrate binding and reaction mechanism". J. Mol. Biol. 273 (3): 714–28. doi:10.1006/jmbi.1997.1331. PMID 9402066.
^ Modis Y, Wierenga RK (October 1999). "A biosynthetic thiolase in complex with a reaction intermediate: the crystal structure provides new insights into the catalytic mechanism". Structure. 7 (10): 1279–90. doi:10.1016/S0969-2126(00)80061-1. PMID 10545327.
^ Middleton B (April 1973). "The oxoacyl-coenzyme A thiolases of animal tissues". Biochem. J. 132 (4): 717–30. PMC 1177647. PMID 4721607.
^ Hovik R, Brodal B, Bartlett K, Osmundsen H (June 1991). "Metabolism of acetyl-CoA by isolated peroxisomal fractions: formation of acetate and acetoacetyl-CoA". J. Lipid Res. 32 (6): 993–9. PMID 1682408.
^ Middleton B, Bartlett K (March 1983). "The synthesis and characterisation of 2-methylacetoacetyl coenzyme A and its use in the identification of the site of the defect in 2-methylacetoacetic and 2-methyl-3-hydroxybutyric aciduria". Clin. Chim. Acta. 128 (2–3): 291–305. doi:10.1016/0009-8981(83)90329-7. PMID 6133656.
^ Kanayama N, Ueda M, Atomi H, Tanaka A (February 1998). "Genetic evaluation of physiological functions of thiolase isoenzymes in the n-alkalane-assimilating yeast Candida tropicalis". J. Bacteriol. 180 (3): 690–8. PMC 106940. PMID 9457876.
^ Price AC, Choi KH, Heath RJ, Li Z, White SW, Rock CO (March 2001). "Inhibition of beta-ketoacyl-acyl carrier protein synthases by thiolactomycin and cerulenin. Structure and mechanism". J. Biol. Chem. 276 (9): 6551–9. doi:10.1074/jbc.M007101200. PMID 11050088.
^ Keatinge-Clay AT, Maltby DA, Medzihradszky KF, Khosla C, Stroud RM (September 2004). "An antibiotic factory caught in action". Nat. Struct. Mol. Biol. 11 (9): 888–93. doi:10.1038/nsmb808. PMID 15286722.
^ Daum RS, Lamm PH, Mamer OA, Scriver CR (December 1971). "A "new" disorder of isoleucine catabolism". Lancet. 2 (7737): 1289–90. doi:10.1016/S0140-6736(71)90605-2. PMID 4143539.
^ Mitchell GA, Fukao T (2001). "Inborn errors of ketone body metabolism". In Scriver CR, Beaudet AL, Sly WS, Valle D. The metabolic & molecular bases of inherited disease. New York: McGraw-Hill. pp. 2326–2356. ISBN 0-07-913035-6.
^ Hillman RE, Keating JP (February 1974). "Beta-ketothiolase deficiency as a cause of the "ketotic hyperglycinemia syndrome"". Pediatrics. 53 (2): 221–5. PMID 4812006.
^ Robinson BH, Sherwood WG, Taylor J, Balfe JW, Mamer OA (August 1979). "Acetoacetyl CoA thiolase deficiency: a cause of severe ketoacidosis in infancy simulating salicylism". J. Pediatr. 95 (2): 228–33. doi:10.1016/S0022-3476(79)80658-7. PMID 36452.

External links

Acetyl-CoA C-Acetyltransferase at the US National Library of Medicine Medical Subject Headings (MeSH)

v t e Transferases: acyltransferases (EC 2.3)

2.3.1: other than amino-acyl groups	acetyltransferases: Acetyl-Coenzyme A acetyltransferase N-Acetylglutamate synthase Choline acetyltransferase Dihydrolipoyl transacetylase Acetyl-CoA C-acyltransferase Beta-galactoside transacetylase Chloramphenicol acetyltransferase N-acetyltransferase Serotonin N-acetyl transferase HGSNAT ARD1A Histone acetyltransferase P300/CBP NAT2 palmitoyltransferases: Carnitine O-palmitoyltransferase CPT1 CPT2 Serine C-palmitoyltransferase SPTLC1 SPTLC2 other: Acyltransferase like 2 Aminolevulinic acid synthase Beta-ketoacyl-ACP synthase Glyceronephosphate O-acyltransferase Lecithin—cholesterol acyltransferase Glycerol-3-phosphate O-acyltransferase 1-acylglycerol-3-phosphate O-acyltransferase 2-acylglycerol-3-phosphate O-acyltransferase ABHD5

2.3.2: Aminoacyltransferases	Gamma-glutamyl transpeptidase Peptidyl transferase Transglutaminase Tissue transglutaminase Keratinocyte transglutaminase Factor XIII

2.3.3: converted into alkyl on transfer	Citrate synthase ATP citrate lyase HMG-CoA synthase Malate synthase

Metabolism: lipid metabolism – ketones/cholesterol synthesis enzymes/steroid metabolism

Mevalonate pathway

To HMG-CoA	Acetyl-Coenzyme A acetyltransferase HMG-CoA synthase (regulated step)

Ketogenesis	HMG-CoA lyase 3-hydroxybutyrate dehydrogenase Thiophorase

To Mevalonic acid	HMG-CoA reductase

To DMAPP	Mevalonate kinase Phosphomevalonate kinase Pyrophosphomevalonate decarboxylase Isopentenyl-diphosphate delta isomerase

Geranyl-	Dimethylallyltranstransferase Geranyl pyrophosphate

To cholesterol

To lanosterol	Farnesyl-diphosphate farnesyltransferase Squalene monooxygenase Lanosterol synthase

7-Dehydrocholesterol path	Lanosterol 14α-demethylase Sterol-C5-desaturase-like 7-Dehydrocholesterol reductase

Desmosterol path	24-dehydrocholesterol reductase

To Bile acids

Steroidogenesis

To pregnenolone

Side-chain cleavage

To corticosteroids

aldosterone: 18-hydroxylase

To sex hormones

To androgens	17α-hydroxylase/17,20 lyase 3β dehydrogenase 17β dehydrogenase 5α reductase 1 2

To estrogens	Aromatase

Other/ungrouped

This article incorporates text from the public domain Pfam and InterPro IPR002155

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Thiolase, N-terminal domain Provide feedback

Thiolase is reported to be structurally related to beta-ketoacyl synthase (PF00109), and also chalcone synthase.

Literature references

Mathieu M, Modis Y, Zeelen JP, Engel CK, Abagyan RA, Ahlberg A, Rasmussen B, Lamzin VS, Kunau WH, Wierenga RK; , J Mol Biol 1997;273:714-728.: The 1.8 A crystal structure of the dimeric peroxisomal 3-ketoacyl-CoA thiolase of Saccharomyces cerevisiae: implications for substrate binding and reaction mechanism. PUBMED:9402066 EPMC:9402066

Internal database links

SCOOP:	ACP_syn_III Chal_sti_synt_N FAE1_CUT1_RppA HMG_CoA_synt_N ketoacyl-synt Peptidase_M22 SpoVAD
Similarity to PfamA using HHSearch:	ketoacyl-synt

External database links

HOMSTRAD:	thiolase
PROSITE:	PDOC00092
SCOP:	1pxt

This tab holds annotation information from the InterPro database.

InterPro entry IPR020616

Two different types of thiolase [PUBMED:1755959, PUBMED:2191949, PUBMED:1354266] are found both in eukaryotes and in prokaryotes: acetoacetyl-CoA thiolase (EC) and 3-ketoacyl-CoA thiolase (EC). 3-ketoacyl-CoA thiolase (also called thiolase I) has a broad chain-length specificity for its substrates and is involved in degradative pathways such as fatty acid beta-oxidation. Acetoacetyl-CoA thiolase (also called thiolase II) is specific for the thiolysis of acetoacetyl-CoA and involved in biosynthetic pathways such as poly beta-hydroxybutyrate synthesis or steroid biogenesis.

In eukaryotes, there are two forms of 3-ketoacyl-CoA thiolase: one located in the mitochondrion and the other in peroxisomes.

There are two conserved cysteine residues important for thiolase activity. The first located in the N-terminal section of the enzymes is involved in the formation of an acyl-enzyme intermediate; the second located at the C-terminal extremity is the active site base involved in deprotonation in the condensation reaction.

Mammalian nonspecific lipid-transfer protein (nsL-TP) (also known as sterol carrier protein 2) is a protein which seems to exist in two different forms: a 14 Kd protein (SCP-2) and a larger 58 Kd protein (SCP-x). The former is found in the cytoplasm or the mitochondria and is involved in lipid transport; the latter is found in peroxisomes. The C-terminal part of SCP-x is identical to SCP-2 while the N-terminal portion is evolutionary related to thiolases [PUBMED:1755959].

Gene Ontology

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

Molecular function	transferase activity, transferring acyl groups other than amino-acyl groups (GO:0016747)
Biological process	metabolic process (GO:0008152)

Domain organisation

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Pfam Clan

This family is a member of clan Thiolase (CL0046), which has the following description:

Thiolases are ubiquitous and form a large superfamily. Thiolases can function either degradatively, in the beta-oxidation pathway of fatty acids, or biosynthetically. Biosynthetic thiolases catalyse the formation of acetoacetyl-CoA from two molecules of acetyl-CoA . This is one of the fundamental categories of carbon skeletal assembly patterns in biological systems and is the first step in a wide range of biosynthetic pathways [1]. Thiolase are usually dimeric or tetrameric enzymes. Within each monomer there are two similar domains related by pseudo dyad. The N-terminal of these two domains contains a large insertion of about 100 amino acids.

The clan contains the following 15 members:

ACP_syn_III ACP_syn_III_C Chal_sti_synt_C Chal_sti_synt_N Docking FAE1_CUT1_RppA HMG_CoA_synt_C HMG_CoA_synt_N KAsynt_C_assoc ketoacyl-synt Ketoacyl-synt_2 Ketoacyl-synt_C SpoVAD Thiolase_C Thiolase_N

Alignments

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	Seed (30)	Full (18983)	Representative proteomes				UniProt (55872)	NCBI (131764)	Meta (6492)
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	Seed (30)	Full (18983)	Representative proteomes				UniProt (55872)	NCBI (131764)	Meta (6492)
	Seed (30)	Full (18983)	RP15 (3133)	RP35 (9638)	RP55 (18567)	RP75 (30000)	UniProt (55872)	NCBI (131764)	Meta (6492)
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	Seed (30)	Full (18983)	Representative proteomes				UniProt (55872)	NCBI (131764)	Meta (6492)
	Seed (30)	Full (18983)	RP15 (3133)	RP35 (9638)	RP55 (18567)	RP75 (30000)	UniProt (55872)	NCBI (131764)	Meta (6492)
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Trees

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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:

Prosite

Previous IDs:

thiolase;

Type:

Domain

Author:

Sonnhammer ELL, Griffiths-Jones SR

Number in seed:

30

Number in full:

18983

Average length of the domain:

243.40 aa

Average identity of full alignment:

30 %

Average coverage of the sequence by the domain:

61.37 %

HMM information

HMM build commands:

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

search method: hmmsearch -Z 26740544 -E 1000 --cpu 4 HMM pfamseq

Model details:

Parameter	Sequence	Domain
Gathering cut-off	26.4	26.4
Trusted cut-off	26.4	26.4
Noise cut-off	26.3	26.3

Model length:

260

Family (HMM) version:

22

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Species distribution

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Colour assignments

Archea	Eukaryota
Bacteria	Other sequences
Viruses	Unclassified
Viroids	Unclassified sequence

Selections

Align selected sequences to HMM

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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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Tree controls

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The tree shows the occurrence of this domain across different species. More...

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:

show/hide the summary boxes
highlight species that are represented in the seed alignment
expand/collapse the tree or expand it to a given depth
select a sub-tree or a set of species within the tree and view them graphically or as an alignment
save a plain text representation of the tree

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Please note: for large trees this can take some time. While the tree is loading, you can safely switch away from this tab but if you browse away from the family page entirely, the tree will not be loaded.

Interactions

There are 6 interactions for this family. More...

Thiolase_C ECH_1 Thiolase_C 3HCDH Thiolase_N 3HCDH_N

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 Thiolase_N domain has been found. There are 307 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...

Family: Thiolase_N (PF00108)

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Summary: Thiolase, N-terminal domain

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Contents

Function

Isozymes

Mechanism

Structure

Biological function

Disease relevance

References

External links

Thiolase, N-terminal domain Provide feedback

Literature references

Internal database links

External database links

InterPro entry IPR020616

Gene Ontology

Domain organisation

Pfam Clan

Alignments

Alignment types

Viewing

Reformatting

Downloading

View options

Format an alignment

Download options

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