D-3-Phosphoglycerate dehydrogenase from Mycobacterium tuberculosis is a link between the Escherichia coli and mammalian enzymes.
D-3-Phosphoglycerate dehydrogenase (PGDH) from Mycobacterium tuberculosis has been isolated to homogeneity and displays an unusual relationship to the Escherichia coli and mammalian enzymes. In almost all aspects investigated, the M. tuberculosis enzyme shares the characteristics of the mammalian PGDHs. These include an extended C-terminal motif, substrate inhibition kinetics, dependence of activity levels and stability on ionic strength, and the inability to utilize alpha-ketoglutarate as a substrate. The unique property that the M. tuberculosis enzyme shares with E. coli PGDH that it is very sensitive to inhibition by L-serine, with an I(0.5) = 30 microm. The mammalian enzymes are not inhibited by L-serine. In addition, the cooperativity of serine inhibition appears to be modulated by chloride ion, becoming positively cooperative in its presence. This is modulated by the gain of cooperativity in serine binding for the first two effector sites. The basis for the chloride modulation of cooperativity is not known, but the sensitivity to serine inhibition can be explained in terms of certain amino acid residues in critical areas of the structures. The differential sensitivity to serine inhibition by M. tuberculosis and human PGDH may open up interesting possibilities in the treatment of multidrug-resistant tuberculosis.
Dey
Sanghamitra
S
Department of Biochemistry & Biophysics, Texas A&M University, College Station, Texas 77843, USA.
Hu
Zhiqin
Z
Xu
Xiao Lan
XL
Sacchettini
James C
JC
Grant
Gregory A
GA
D020816:Amino Acid Motifs; D000595:Amino Acid Sequence; D000818:Animals; D001665:Binding Sites; D002237:Carbohydrate Dehydrogenases / Q000737:chemistry / Q000502:physiology*; D002712:Chlorides / Q000737:chemistry; D003001:Cloning, Molecular; D004305:Dose-Response Relationship, Drug; D018432:Drug Resistance, Multiple; D004591:Electrophoresis, Polyacrylamide Gel; D004926:Escherichia coli / Q000201:enzymology / Q000378:metabolism*; D006801:Humans; D007477:Ions; D007700:Kinetics; D008099:Liver / Q000201:enzymology; D008957:Models, Genetic; D008969:Molecular Sequence Data; D009169:Mycobacterium tuberculosis / Q000201:enzymology*; D050543:Phosphoglycerate Dehydrogenase; D011189:Potassium Chloride / Q000737:chemistry; D011485:Protein Binding; D017434:Protein Structure, Tertiary; D051381:Rats; D017386:Sequence Homology, Amino Acid; D012694:Serine / Q000737:chemistry; D013379:Substrate Specificity; D013997:Time Factors
D002712:Chlorides; D007477:Ions; D012694:Serine; D011189:Potassium Chloride; D002237:Carbohydrate Dehydrogenases; D050543:Phosphoglycerate Dehydrogenase