GLYCOGEN METABOLISM
Glycogen is the main reserve homopolysaccharide of a human. A monomer of glycogen is glucose. Glucose residues are connected in linear chains by 1,4-a-glycoside bonds. Branches are formed by1,6-a-glycoside bonds. The branched structure of glycogen causes many terminal monomers. It is important for enzymes working at glycogen decay or synthesis. Glycogen is deposited in the liver and skeletal muscle and stored in the cytosol in the form of pellets. Metabolic pathways of glycogen synthesis and degradation are different.
Glycogen synthesis (glycogenesis) occurs within 1-2 hours after intake of carbohydrate foods and requires consumption of ATP. This process reduces the glucose level in the blood.
1). Phosphorylation of glucose with the participation of hexokinase (in muscle) and glucokinase (in liver) gives glucose-6-phosphate, which transforms into glucose-1-phosphate (enzyme is phosphoglukomutase):
2). Glucose-1-phosphate reacts with UTP with the participation of glucose-1-phosphate uridil transferase. UDP-glucose and pyrophosphate are formed:
3). Transfer of glucose residue from UDP-glucose to a small fragment of pre-existing glycogen chain (“primer”) goes under the action of glycogen synthase:
UDP-G + glycogen (n) ® UDP + glycogen (n+ 1)
Glycogen synthase catalyzes the formation of a-1,4-glycosidic bonds. In the absence of glycogen a specific protein glycogenin can accept glucose from UDP-glucose.
Glycogen branching enzyme (glucosyl α-4,6 transferase) provides formation of 1,6-α glycosidic bonds. It transfers the oligosaccharide fragments (6-7 glucose residues) to the 6-hydroxyl group of glucose residue of the same or different chains of glycogen where it is linked by α-1,6-bond.
The degradation of glycogen (glycogenolysis) is a conversion of glycogen from reserve form in the metabolic form (glucose). In the presence of phosphorylase glycogen is degraded into glucose-1-phosphate without splitting on fragments.
Glycogen phosphorylase exists in two forms - phosphorylase a (active) and phosphorylase b (inactive). Both forms can dissociate into subunits. Phosphorylase b consists of two subunits, phosphorylase a consists of 4 subunits. The conversion of phosphorylase a into phosphorylase b is accomplished by phosphorylation of protein under the action of phosphorylase kinase:
2 Phosphorylase b + 4 ATP → phosphorylase a + 4 ADP.
Inactive phosphorylase kinase becomes active under the influence of the enzyme cAMP-dependent protein kinase. cAMP is formed from ATP under the action of adenylate cyclase that is activated by adrenalin and glucagon. As a result, glycogen breaks down and forms glucose-1-phosphate.
A limit dextrin is formed, which is cleaved under the action of a bifunctional enzyme (debranching enzyme). It has transferase activity and α-1,6-glucosidase activity and releases a free glucose. Then glycogen again can be degraded by phosphorylase.
Glucose-1-phosphate under the influence of phosphoglucomutase is converted into glucose 6-phosphate. Glucose is formed in the liver from glucose-6-phosphate by hydrolytic cleavage of phosphate (enzyme is glucose-6-phosphatase).
G-1-P ® G-6-P ® G
GLYCOLYSIS
Glycolysis (Embden – Meyerhof pathway)is the sequence of enzymatic reactions that lead to the splitting of glucose with the formation of pyruvic acid or lactate, accompanied by the formation of ATP. This process occurs in the cell cytosol.
In aerobic glycolysis pyruvate is formed. It enters the mitochondria, and further, in the common catabolic pathway, is oxidized to CO2 and H2O. Aerobic glycolysis is the part of aerobic degradation of glucose.
In anaerobic glycolysis pyruvate is formed and then is converted to lactate. Anaerobic degradation of glucose and anaerobic glycolysis are synonyms. Anaerobic glycolysis occurs in the first few minutes of muscular work, in erythrocytes (there are no mitochondria in erythrocytes), and when there is insufficient intake of oxygen.
Reactions of glycolysis:
1). Phosphorylation of glucose. The reaction is catalyzed by hexokinase, in parenchymal liver cells it is catalyzed by glucokinase. The formation of glucose-6-phosphate in the cell is a trap for glucose, because membrane is impermeable for phosphorylated glucose. It is irreversible reaction. Hexokinase has low Km, glucokinase has high Km.
2). Isomerization reaction is catalyzed by glucose-6-phosphate isomerase (phosphoglucose isomerase):
3) Phosphorylation reaction is catalyzed by 6-phosphofructokinase. This is irreversible and the rate-limiting reaction.
These three reactions are reactions of energy investment phase.
4).Aldol splitting reaction is catalyzed by aldolase.
5). Isomerization of dihydroxyacetonephosphate is catalyzed by enzyme triosephosphate isomerase:
1 molecule of glucose is converted to 2 molecules of glyceraldehyde-3-phosphate (reactions 4, 5). This was splitting phase.
The next stage is energy generation phase.
6).The oxidation of glyceraldehyde-3-phosphate goes under the action of enzyme glyceraldehyde-3-phosphate dehydrogenase:
7). Substrate level phosphorylation goes on with the participation of phosphoglycerate kinase:
8).Intramolecular transfer of a phosphate group. The enzyme is phosphoglycerate mutase:
9). Dehydration with the participation of enolase:
10). Substrate level phosphorylation. The enzyme is pyruvate kinase:
This is irrevesible reaction.
11).Under anaerobic conditions, the reduction of pyruvate to lactate occurs. Reaction is catalyzed by lactate dehydrogenase:
The overall equation of anaerobic glycolysis:
glucose + 2 NAD+ + 2 ADP + 2 Pi®2 pyruvate + 2 NADH + 2 ATP
Anaerobic glycolysis does not require the mitochondrial respiratory chain.
The yield of ATP from anaerobic glycolysis: ATP is formed in two reactions of substrate level phosphorylation. 4 ATP molecules are formed by 1 glucose molecule (1 glucose molecule gives 2 trioses, and each gives 2 ATP in 7th and 10th reactions of glycolysis.). 2 ATP are consumed (reaction 1 and 3 of glycolysis) and
4 ATP - 2 ATP = 2 ATP.
The yield of ATP in aerobic degradation of glucose:
- three reactions of substrate level phosphorylation (7th, 10th - glycolysis; 5th – Krebs cycle) = 3ATP;
- five reactions of dehydrogenation with the formation of NADH (6th - glycolysis, 3rd - oxidative decarboxylation of pyruvate; 3rd, 4th, 8th - Krebs cycle) Þ 3x5 = 15ATP;
- dehydrogenation reaction (6th - Krebs cycle) with the formation of FADH2 = 2 ATP;
total: 3ATP + 15 ATP + 2ATP= 20 ATP.
From 1 molecule of glucose 2 molecules of glyceraldehydes-3-phosphate are produced, then 2х20ATP = 40 ATP.
In reactions 1 and 3 of glycolysis 2ATP are consumed, and
40ATP - 2ATP = 38ATP.
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