Enzyme dysfunction at atomic resolution: Disease-associated variants of human phosphoglucomutase-1

Area of Science:

• Biochemistry
• Structural Biology
• Human Genetics

Background:

• Missense variants in proteins can cause distinct biochemical phenotypes, impacting enzyme function and leading to genetic diseases.
• Phosphoglucomutase-1 (PGM1) deficiency is an inborn error of metabolism linked to specific protein variants.
• Structural characterization of protein variants is becoming more feasible, offering insights into disease mechanisms.

Purpose of the Study:

• To review four examples of enzyme dysfunction in disease-related variants of PGM1.
• To highlight the synergy between structural and biochemical studies in understanding missense variant pathomechanisms.
• To demonstrate how experimental characterization provides richer insights than predictive algorithms.

Main Methods:

• Analysis of 11 crystal structures of wild-type (WT) and mutant PGM1 enzymes.
• Performance of multiple biochemical assays to assess enzyme activity and stability.
• Comparative structural analysis between WT and mutant PGM1 variants.

Main Results:

• Disease-related PGM1 variants exhibit distinct biochemical and structural alterations compared to WT.
• Structural studies reveal specific molecular pathomechanisms underlying PGM1 deficiency.
• Experimental data provide a detailed understanding of enzyme dysfunction caused by missense variants.

Conclusions:

• Experimental structural and biochemical studies are crucial for elucidating the pathomechanisms of genetic diseases caused by protein variants.
• Comparing WT and mutant structures offers valuable insights into enzyme function and dysfunction.
• Studying pathogenic variants can also illuminate the function of the wild-type enzyme.