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Classification and substrate head-group specificity of membrane fatty acid desaturases

View Article: PubMed Central - PubMed

ABSTRACT

Membrane fatty acid desaturases are a diverse superfamily of enzymes that catalyze the introduction of double bonds into fatty acids. They are essential in a range of metabolic processes, such as the production of omega-3 fatty acids. However, our structure–function understanding of this superfamily is still developing and their range of activities and substrate specificities are broad, and often overlapping, which has made their systematic characterization challenging. A central issue with characterizing these proteins has been the lack of a structural model, which has been overcome with the recent publication of the crystal structures of two mammalian fatty acid desaturases. In this work, we have used sequence similarity networks to investigate the similarity among over 5000 related membrane fatty acid desaturase sequences, leading to a detailed classification of the superfamily, families and subfamilies with regard to their function and substrate head-group specificity. This work will facilitate rapid prediction of the function and specificity of new and existing sequences, as well as forming a basis for future efforts to manipulate the substrate specificity of these proteins for biotechnology applications.

No MeSH data available.


The surface charge distribution comparison between an acyl-CoA-specific FD-A and an MGDG-specific FD-C. The difference in surface charge distributions visualized on the surface of the crystal structure of human steaoryl-CoA Δ9 desaturase (SCD1, PDB ID: 4ZYO) and the homology model of ADS1 inside and around the substrate-binding cavity.
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f0025: The surface charge distribution comparison between an acyl-CoA-specific FD-A and an MGDG-specific FD-C. The difference in surface charge distributions visualized on the surface of the crystal structure of human steaoryl-CoA Δ9 desaturase (SCD1, PDB ID: 4ZYO) and the homology model of ADS1 inside and around the substrate-binding cavity.

Mentions: Although both FD-A and FD-C clusters belong to the FD family, they have diverged in terms of head-group specificity. When the sequence differences between the FD-A human SCD1 and the FD-C ADS1 and are compared, a number of non-conservative substitutions are evident (Fig. 4). Specifically, a number of charged or polar residues that are responsible for CoA binding in SCD1 are replaced by uncharged amino acids in ADS1, which result in significant changes in the surface charge distribution in the substrate binding cavity (Fig. 5). The loss of positive charge, which is complementary to the extensive negative charge on coenzyme-A but is not required for binding of the glycerol-sugar moiety of MGDG, is consistent with the change in specificity.


Classification and substrate head-group specificity of membrane fatty acid desaturases
The surface charge distribution comparison between an acyl-CoA-specific FD-A and an MGDG-specific FD-C. The difference in surface charge distributions visualized on the surface of the crystal structure of human steaoryl-CoA Δ9 desaturase (SCD1, PDB ID: 4ZYO) and the homology model of ADS1 inside and around the substrate-binding cavity.
© Copyright Policy - CC BY
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC5037126&req=5

f0025: The surface charge distribution comparison between an acyl-CoA-specific FD-A and an MGDG-specific FD-C. The difference in surface charge distributions visualized on the surface of the crystal structure of human steaoryl-CoA Δ9 desaturase (SCD1, PDB ID: 4ZYO) and the homology model of ADS1 inside and around the substrate-binding cavity.
Mentions: Although both FD-A and FD-C clusters belong to the FD family, they have diverged in terms of head-group specificity. When the sequence differences between the FD-A human SCD1 and the FD-C ADS1 and are compared, a number of non-conservative substitutions are evident (Fig. 4). Specifically, a number of charged or polar residues that are responsible for CoA binding in SCD1 are replaced by uncharged amino acids in ADS1, which result in significant changes in the surface charge distribution in the substrate binding cavity (Fig. 5). The loss of positive charge, which is complementary to the extensive negative charge on coenzyme-A but is not required for binding of the glycerol-sugar moiety of MGDG, is consistent with the change in specificity.

View Article: PubMed Central - PubMed

ABSTRACT

Membrane fatty acid desaturases are a diverse superfamily of enzymes that catalyze the introduction of double bonds into fatty acids. They are essential in a range of metabolic processes, such as the production of omega-3 fatty acids. However, our structure–function understanding of this superfamily is still developing and their range of activities and substrate specificities are broad, and often overlapping, which has made their systematic characterization challenging. A central issue with characterizing these proteins has been the lack of a structural model, which has been overcome with the recent publication of the crystal structures of two mammalian fatty acid desaturases. In this work, we have used sequence similarity networks to investigate the similarity among over 5000 related membrane fatty acid desaturase sequences, leading to a detailed classification of the superfamily, families and subfamilies with regard to their function and substrate head-group specificity. This work will facilitate rapid prediction of the function and specificity of new and existing sequences, as well as forming a basis for future efforts to manipulate the substrate specificity of these proteins for biotechnology applications.

No MeSH data available.