Fatty acid synthase, inhibitors and modifications thereof and its use
Inventors
Chari, Ashwin • Stark, Holger • SINGH, Kashish • GRAF, Benjamin Moritz
Assignees
Max Planck Gesellschaft Zur Foerderund Der Wissenschaften EV • Max-Planck-Gesellschaft zur Förderung der Wissenschaften eV
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Publication Number
US-12509682-B2
Publication Date
2025-12-30
Expiration Date
Abstract
In a first aspect, the present invention relates to new recombinant polypeptides derived from the newly identified gamma subunit of the fatty acid synthase protein complex. In addition, a fatty acid synthase protein complex comprising these new recombinant polypeptides are disclosed as well as nucleic acid molecules encoding these polypeptides. Further, a host cells containing the nucleic acid molecule encoding the polypeptides according to the present invention or expressing the polypeptide according to the present invention are described. In addition, an isolated fatty acid synthase protein complex is disclosed containing the newly identified gamma subunit thereof. Moreover, methods for determining the suitability of candidate compounds capable of inhibiting either the ketoreductase, enoylreductase or malonyl/palmitoyl transferase present in the FAS protein complex and methods for designing inhibitors of said enzymes are disclosed. Finally, the present invention relates to the inhibitors and their use in medicinal applications.
Core Innovation
The invention identifies Tma17p as a bona fide yeast fatty acid synthase (FAS) γ-subunit and describes how the γ-subunit is incorporated into a FAS holoenzyme context. Recombinant γ-subunit-derived polypeptides are provided, including sequences based on SEQ ID NO: 1 fragments with an insert positioned C-terminally relative to amino acid 112. Nucleic acids and host cells encoding the recombinant polypeptides are also described.
Functionally, γ-subunit binding is stated to alter FAS structure and substrate kinetics. Structural studies using cryo-electron microscopy and X-ray crystallography are described as showing a rotated/compacted FAS conformation stabilized by the γ-subunit, with ACP domain repositioning and specific steric occlusion/competition at ER and KR active sites.
The kinetics discussion further states partial inhibition of acetyl-CoA and malonyl-CoA binding and a γ-subunit-dependent NADPH kinetic shift. The described work also supports inhibitor discovery/design approaches targeting FAS enzymes, including KR, ER, and MPT, using crystallography and/or cryo-EM to assess candidate compounds.
Claims Coverage
One independent claim (clm-00001) is provided, focusing on a recombinant polypeptide defined by regions derived from SEQ ID NO: 1 plus a C-terminally located insert. The independent claim is supported by dependent claims that refine insert composition, size, and arrangement, and by further dependents that expand scope to fatty acid synthase protein complexes containing the recombinant polypeptide.
Recombinant polypeptide with SEQ ID NO: 1 N-terminal region and C-terminal insert
A recombinant polypeptide containing amino acid 1 to amino acid 112 of SEQ ID NO: 1, comprising an insert located C-terminally to amino acid 112 of SEQ ID NO: 1, wherein the insert is at least 50 amino acids in length, optionally comprising at least one amino acid from amino acid 113 to amino acid 150 of SEQ ID NO: 1.
Insert as an enzyme
The recombinant polypeptide in which the insert is an enzyme.
Insert enzyme classes selected from desaturase, thioesterase, oxygenase, hydroxylase, cyclogenase, and fatty acid lyase
The recombinant polypeptide in which the enzyme is selected from a desaturase, thioesterase, oxygenase, hydroxylase, cyclogenase, and fatty acid lyase.
Insert size constrained to at most 40 kDa
The recombinant polypeptide in which the size of the insert is at most 40 kDa.
The claim set centers on recombinant polypeptides defined by an SEQ ID NO: 1-derived N-terminal region (amino acids 1–112) and a C-terminally located insert of at least 50 amino acids, with optional inclusion of SEQ ID NO: 1 residues 113–150. Dependent claims further constrain the insert by specifying it as an enzyme, limiting enzyme class to those listed, and setting an upper bound on insert size.
Stated Advantages
Not explicitly described in patent.
Documented Applications
Not explicitly described in patent.
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