Relationship between Metabolic Fluxes and Sequence-Derived Properties of Enzymes

Abstract

Metabolic fluxes are key parameters of metabolic pathways being closely related to the kinetic properties of enzymes, thereby could be dependent on. This study examines possible relationships between the metabolic fluxes and the physical-chemical/structural features of enzymes from the yeast Saccharomyces cerevisiae glycolysis pathway. Metabolic fluxes were quantified by the COPASI tool using the kinetic models of Hynne and Teusink at varied concentrations of external glucose. The enzyme sequences were taken from the UniProtKB and the average amino acid (AA) properties were computed using the set of Georgiev's uncorrelated scales that satisfy the VARIMAX criterion and specific AA indices that show the highest correlations with those. Multiple linear regressions (88.41% <R adjusted 2 < 93.32%; P < 0.00001) were found between the values of metabolic fluxes and the selected sets of the average AA properties. The hydrophobicity, α-helicity, and net charge were pointed out as the most influential characteristics of the sequences. The results provide an evidence that metabolic fluxes of the yeast glycolysis pathway are closely related to certain physical-chemical properties of relevant enzymes and support the view on the interdependence of catalytic, binding, and structural AA residues to ensure the efficiency of biocatalysts and, hence, physiologically adequate metabolic processes.

Key aspects of the past 30 years of protein design

“…It has been proved that a protein function, such as the catalytic activity of an enzyme, depends on the interaction between specific sequence positions and exhibits a balance between structural stability and flexibility. Also, it is challenging to classify residues as strictly functional or structural due to a correspondence between these two categories; their mutual correlation is essential for the protein activity [305,306]. It is meant by strictly structural residues such as amino acids responsible for protein stability.…”

“…An accurate characterization of structural and functional protein residues is fundamental for developing proteome mapping, protein engineering, and new pharmaceutical applications based on the design of target protein [307][308][309][310][311]. The experimental identification of residues is a time-consuming and expensive process: a high-throughput tool requires a large scale mutation assay [306,307], whereas in silico screening has a lower cost. Several computational methods [313][314][315][316][317][318] have been developed for studying protein evolution.…”

“…Also, It is challenging to classify residues as strictly functional or structural due to a correspondence between these two categories; their mutual correlation is essential for the protein activity. [307,308] It is meant by strictly structural residues such as amino acids responsible for protein stability. The loss of the folded structure can affect the functionality of the protein.…”

Identification of Protein Functional Regions

“…More precisely, it has been shown that for a protein to function, e. g. for the catalytic activity of enzymes, the sequence must contain explicit interacting spots and, simultaneously, show a balance between structural stability and flexibility. Despite the intuition might lead to concluding that structure and function evolved independently and, as a consequence, each residue can be classified as strictly functional or strictly structural, several studies showed that there is an overlap between the two categories and the interdependence is essential for the protein activity …”