Fatty Acid Synthase

 

What InterPro Tells Us

P49327 Human Fatty acid synthase

 

InterPro Domain Architecture

 

InterPro Entry

Signatures

Graphical Match

IPR014030

PF00109

IPR014030

PS00606

IPR014031

PF02801

IPR016038

G3DSA:3.40.47.10

IPR016039

SSF53901

IPR014043

PF00698

IPR001227

G3DSA:3.40.366.10

IPR016035

SSF52151

IPR016036

SSF55048

IPR013217

PF08242

IPR011032

SSF50129

IPR013149

PF00107

IPR002198

PF00106

IPR016040

G3DSA:3.40.50.720

IPR016040

SSF51735

IPR006162

PS00012

IPR006163

PF00550

IPR006163

PS50075

IPR009081

G3DSA:1.10.1200.10

IPR009081

SSF47336

IPR001031

PF00975

IPR000794

PTHR11712

Structural Features

 

 

PDB

2jfd (chains A-D)

PDB

2cq5 (chain B)

PDB

1xkt (chains A, B)

CATH

1xktA02

CATH

1xktA01

SCOP

d1xkta

Structural Predictions

 

 

ModBase

MB_P49327

 

From the graphical match in the table above, you can see that the signatures are grouped into thirteen InterPro entries for human fatty acid synthase.  InterPro entries group together all the signatures that represent the same sequence found in the same set of proteins.  These entries provide a family hierarchy of fatty acid synthase proteins, as well as identifying the domain organisation and sequence features of this protein. 

 

FAMILY Entries

Ø      IPR000794: Beta-ketoacyl synthase, represented by one signature: PTHR11712 (PANTHER).

This entry places FAS enzymes in the same family as several ketoacyl synthases and polyketide synthases.

 

DOMAIN Entries

1)      Beta-ketoacyl synthase domain (KS; EC 2.3.1.41):

Ø      IPR014030: N-terminal subdomain, represented by two signatures: PF00109 (PFAM), PS00606 (PROSITE).

Ø      IPR014031: C-terminal subdomain, represented by one signature: PF02801 (PFAM). 

Ø      IPR016038: Thiolase-like domain subgroup, represented by one signature: G3DSA:3.40.47.10 (GENE3D). 

Ø      IPR016039: Thiolase-like domain, represented by one signature: SSF53901 (SUPERFAMILY). 

 

2)      Malonyl transacylase (MPT; EC 2.3.1.39) and possible dehydratase (DH; EC 4.2.1.61)

Ø      IPR014043: Acyl/malonyl transferases domain, represented by one signature: PF00698 (PFAM). 

Ø      IPR001227: Acyl/malonyl transferases region, represented by one signature: G3DSA:3.40.366.10 (GENE3D). 

Ø      IPR016035: Acyl transferase/acyl hydrolase/lysophospholipase, represented by one signature: SSF52151 (SUPERFAMILY)

-         This is one domain with two catalytic active sites:

-         Active site residue (malonyl transferase; EC 2.3.1.39) = 581

-         Active site residue (beta-hydroxyacyl dehydratase; possibly EC 4.2.1.61) = 878

Ø      IPR016036: ACP-binding region of malonyl transacylase, represented by one signature: SSF55048 (SUPERFAMILY)

 

3)      Domain

Ø      IPR013217: Methyltransferase type 12 domain, represented by one signature: PF08242 (PFAM).

 

4)      Enoyl reductase domain (ER; EC 1.3.1.10):

Ø      IPR011032: GroES-like domain, represented by one signature: SSF50129 (SUPERFAMILY). 

-         The N-terminal domain of several alcohol dehydrogenases has a GroES-like fold

Ø      IPR013149: Alcohol dehydrogenase domain, represented by one signature: PF00107 (PFAM).

-         This is the enoyl reductase domain

-         Nucleotide binding site for NADPH = 1671-1688

Ø      IPR016040: NAD(P)-binding domain, represented by two signatures:  G3DSA:3.40.50.720 (GENE3D), SSF51735 (SUPERFAMILY)

-         This entry identifies domains that bind NAD or NADP. The enoyl reductase domain is known to use NADPH.

 

5)      Beta-ketoacyl reductase domain (KR; EC 1.1.1.100):

Ø      IPR002198: Represented by four signatures: PF00106 (PFAM), PR00080 (PRINTS), PS00061 (PROSITE), PTHR19410 (PANTHER). 

-         Nucleotide binding site for NADPH = 1886-1901

Ø      IPR016040: NAD(P)-binding domain, represented by two signatures:  G3DSA:3.40.50.720 (GENE3D), SSF51735 (SUPERFAMILY)

-         This entry identifies domains that bind NAD or NADP. The beta-ketoacyl reductase domain is known to use NADPH.

 

6)      Acyl carrier protein (ACP):

Ø      IPR006162: Phosphopantheine attachment site, represented by one signature: PS00012 (PROSITE).

-         PROSITE predicts phosphopantheine attachment site for ACP to be between residues 2151-2166 (known to be at 2156)

Ø      IPR006163: Phosphopantheine-binding domain, represented by two signatures: PF00550 (PFAM), PS50075 (PROSITE).

Ø      IPR009081: Acyl carrier protein-like domain, represented by two signatures: G3DSA:1.10.1200.10 (GENE3D), SSF47336 (SUPERFAMILY).

 

7)      Thioesterase domain (possibly EC 3.1.2.14):

Ø      IPR001031: Thioesterase domain, represented by one signature: PF00975 (PFAM).

-         Active site residues = 2308, 2481

 

The graphical match shows that human fatty acid synthase can be subdivided into nine regions (as covered by non-overlapping signatures in the table), which represent seven catalytic domains and the acyl carrier protein (ACP).  The enzyme activities can be linked up with most of these regions (as given).  In certain cases, active sites and binding sites have been identified by UniProt - this additional information is provided above.

In some cases, there are multiple entries covering the same sequence, but assigned to different entries.  This is because, although the signatures cover the same sequence, some signatures hit additional proteins, which provides a family/sub-family grouping for these domains.  For instance, IPR016035 covers the malonyl transacylase (MPT) domain (an acyl transferase), but the signature represents a structural domain with a 3-layer alpha/beta/alpha topology that is also found in acyl hydrolases and in lysophospholipases. Therefore it is the PARENT of the more specific entry IP001227, which only covers acyl transferases.  IPR001227 is in turn the PARENT of the even more specific entry IPR014043 that only covers specific acyl transferases.  This hierarchical scheme represents the evolutionary divergence of domain sequences.

Similarly, both IPR016038 and IPR016039 represent the thiolase-like family of domains, which includes the domain found in beta-ketoacyl synthase.  This domain forms two subdomains, each represented by a different entry (IPR014030 and IPR014031).

 

Structural features

The remaining seven entries in the table above give information on the known and predicted structure of this protein.  These entries presents known structural data from the structural database PDB (green stripe) and the structural classification databases CATH (pink stripe) and SCOP (black stripe) (the names such as 1xktA02 are derived from the PDB entry upon which they are based, here PDB entry 1xkt, chain A, region 2), as well as predicted structural data from the homology model databases ModBase (yellow stripe).  The graphical match for the PDB entries 2jfd, 2cq5, 1xkt display the full length of the original PDB entries, here covering only small regions of the protein.  The ModBase homology model (MB_P49327) provides predicted structure for the remainder for the protein.

The PDB entry 1xkt has been classified by both CATH and SCOP, although their classification varies from one another.  SCOP (d1xkta) classifies the region covered by 1xkt as one functional domain having a 3-layer alpha/beta/alpha topology.  CATH classifies the region covered by 1xkt as two structural subdomains, where 1xktA01 subdomain has a Rossmann-like fold and 1xktA02 insert subdomain has an orthogonal bundle fold.

 

What the Structure Tells Us

 

            Structures associated with the human fatty acid synthase can be viewed using AstexViewer®, which is linked from the Match Table via the logo  on the InterPro page (please note, there is no link directly from this page to the AstexViewer®, therefore you need to go to the  link on the InterPro page for P49327).  The AstexViewer® displays the full PDB structure for the thioesterase domain.  Note that there are two copies of this domain present (i.e. shown as a dimer).

There are structures available for several different fatty acid synthases from a variety of organisms in the Protein Data Bank (PDB), both as type I multi-functional enzymes, as well as type II individual enzymes.  A detailed description and visualisation of the structural features of fatty acid synthases can be found at the PDB ‘Molecule of the Month’.  The crystallographic structures of various fatty acid synthases have provided insight into their mechanism of action.

 

 

 

AstexView of human fatty acid synthase, thioesterase domain:

(shown as a dimer).

 

Next:   Table of Fatty Acid Synthases

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