Assignment 1: Metabolism Gone Wrong: Galactosemia
Course: Biochem 3D03
TA: Rabia Mateen
Name: Kei Cheng Mak
ID: 3122260
Date: October 15th, 2014
Introduction Metabolism consists of biochemical reactions catalyzing the conversion of complex macronutrients into usable energy by various enzymes. Energy in food is extracted from three macronutrients - carbohydrate, protein and fat. As food passes through the digestive tract, various enzymes and chemicals in the body break food particles into macronutrients and macronutrients. Macronutrients are the energy providers that are further processed into glucose, amino acids and fatty acids. Unlike glucose, fats and amino acids need to be first converted into an intermediate product of glycolysis …show more content…
Intermediate substances accumulate causing toxic effects, and a reduction or absence of some essential products. Enzyme dysfunctions caused by genetic abnormalities interfere with the body 's metabolism. Missing or non-functioning enzymes in the metabolic pathway cause metabolic disorders, which are potentially lethal if left untreated.
Galactosemia Galactosemia is hereditary autosomal recessive metabolic disorder triggered by missing or non-functioning galactose-1-phosphate uridyl transferase (GALT) (Berry, 2012). GALT deficiency results in a disorder known as galactosemia, which happens in three forms including classic galactosemia, clinical variant galactosemia and biochemical variant galactosemia. Classic galactosemia, characterized by mutation Q188R, is associated with reduced or absence of GALT enzyme activity. It is the most common and severe form of galactosemia. Patients with S135L mutation are classified in the second type of galactosemia - Clinical variant galactosemia. The symptoms associate with …show more content…
3D structure of GALT from Escherichia coli at 1.8 A resolution. PYMOL: 1HXP. GALT is a homodimer with an active site, iron II and zinc II ion on each chemically identical subunit. Each subunit contains a domain with a half-barrel of nine strands of antiparallel beta-sheet (Wedekind et al, 1995). Two amphipathic alpha helices span the hydrophobic region of the barrel. Iron II ion, coordinated by three histidine residues, resides outside the beta barrel to stabilize the interface of the subunit. Two cysteine and histidine residues coordinate zinc II ion which helps to orient residues into the active site.
Source: McCorvie, T. J.; Timson, D. J. The structural and molecular biology of type I galactosemia: Enzymology of galactose 1-phosphate uridylyltransferase. 2011, 63, 694-700.
Figure 3. Mechanism of GALT catalyzed conversion of galactose-1-phosphate to glucose-1-phospahte catalyzed through ping-pong mechanism. GALT catalyzes the transfer of UMP group from UDP-glucose to galactose-1-phosphate via substituted enzyme mechanism. The histidine residue in the active site of GALT attacks UDP-glucose, forming glucose-1-phosphate and enzyme-UMP adduct at the active. Enzyme-UMP is an intermediate that reacts further in the reaction. Enzyme-UMP adduct reacts with galactose-1-phosphate to produce UDP-galactose. In the end of the reaction, enzyme-UMP adduct returns to GALT and ready to participate in the next reaction (McCorvie et al.
Course: Biochem 3D03
TA: Rabia Mateen
Name: Kei Cheng Mak
ID: 3122260
Date: October 15th, 2014
Introduction Metabolism consists of biochemical reactions catalyzing the conversion of complex macronutrients into usable energy by various enzymes. Energy in food is extracted from three macronutrients - carbohydrate, protein and fat. As food passes through the digestive tract, various enzymes and chemicals in the body break food particles into macronutrients and macronutrients. Macronutrients are the energy providers that are further processed into glucose, amino acids and fatty acids. Unlike glucose, fats and amino acids need to be first converted into an intermediate product of glycolysis …show more content…
Intermediate substances accumulate causing toxic effects, and a reduction or absence of some essential products. Enzyme dysfunctions caused by genetic abnormalities interfere with the body 's metabolism. Missing or non-functioning enzymes in the metabolic pathway cause metabolic disorders, which are potentially lethal if left untreated.
Galactosemia Galactosemia is hereditary autosomal recessive metabolic disorder triggered by missing or non-functioning galactose-1-phosphate uridyl transferase (GALT) (Berry, 2012). GALT deficiency results in a disorder known as galactosemia, which happens in three forms including classic galactosemia, clinical variant galactosemia and biochemical variant galactosemia. Classic galactosemia, characterized by mutation Q188R, is associated with reduced or absence of GALT enzyme activity. It is the most common and severe form of galactosemia. Patients with S135L mutation are classified in the second type of galactosemia - Clinical variant galactosemia. The symptoms associate with …show more content…
3D structure of GALT from Escherichia coli at 1.8 A resolution. PYMOL: 1HXP. GALT is a homodimer with an active site, iron II and zinc II ion on each chemically identical subunit. Each subunit contains a domain with a half-barrel of nine strands of antiparallel beta-sheet (Wedekind et al, 1995). Two amphipathic alpha helices span the hydrophobic region of the barrel. Iron II ion, coordinated by three histidine residues, resides outside the beta barrel to stabilize the interface of the subunit. Two cysteine and histidine residues coordinate zinc II ion which helps to orient residues into the active site.
Source: McCorvie, T. J.; Timson, D. J. The structural and molecular biology of type I galactosemia: Enzymology of galactose 1-phosphate uridylyltransferase. 2011, 63, 694-700.
Figure 3. Mechanism of GALT catalyzed conversion of galactose-1-phosphate to glucose-1-phospahte catalyzed through ping-pong mechanism. GALT catalyzes the transfer of UMP group from UDP-glucose to galactose-1-phosphate via substituted enzyme mechanism. The histidine residue in the active site of GALT attacks UDP-glucose, forming glucose-1-phosphate and enzyme-UMP adduct at the active. Enzyme-UMP is an intermediate that reacts further in the reaction. Enzyme-UMP adduct reacts with galactose-1-phosphate to produce UDP-galactose. In the end of the reaction, enzyme-UMP adduct returns to GALT and ready to participate in the next reaction (McCorvie et al.