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Chapter 16 Biochem
Terms in this set (67)
How does ATP act as an effector on phosphofructokinase?
-high levels of ATP allosterically inhibit the enzyme by binding to a specific regulatory site which lowers the enzyme's affinity for fructose-6-phosphate
What does glycolysis start with and end with?
-a glucose molecule is turned into pyruvate
What is the first stage of glycolysis?
-glucose is trapped, destabilized and cleaved into two interconvertible three-carbon molecules, generated by the cleavage of six-carbon fructose
What is the second stage of glycolysis?
-the three-carbon units are oxidized to pyruvate, generating ATP
What is the one principal fate of glucose once its inside the cell?
-its phosphorylated by ATP to form glucose 6-phosphate
What enzyme phosphorylates glucose and what are two purposes for the phosphorylation?
1) it is the committed step which locks glucose into metabolism
2) the addition of the phosphoryl group facilitates the metabolism of glucose to the phosphorylated three-carbon compounds with high phosphoryl-transfer potential
What does hexokinase require to phosphorylate glucose?
-Mg²⁺, or another divalent metal like Mn2+, that can form a complex with ATP
What is the reason for substrate-induced cleft closing in kinases?
-The two lobes of hexokinase are separated in the absence of glucose; but when glucose binds the conformation of hexokinase changes and the two lobes of the enzyme come together
-The environment around glucose becomes more nonpolar as water is extruded and the hydrophobic R groups of the protein surround the glucose molecule, which favors the donation of the terminal phosphoryl group of ATP
What is the purpose of the isomerization of glucose-6-P to fructose-6-P?
-it is a conversion of an aldose (glucose-6-phosphate) into a ketose (fructose-6-phosphate)
-glucose-6-phosphate is not readily cleaved into two three-carbon fragments, whereas fructose-6-phosphate is
What is the enzyme responsible for the key regulatory step in glycolysis?
What is fructose-6-phosphate phosphorylated by and what does it form?
-phosphorylated by ATP to form fructose 1,6-bisphosphate
Through the action of the enzymes aldolase and triose phosphate isomerase (TIM), one equivalent of fructose-1,6-bisphosphate is made into how many equivalents of what molecule?
-made into two triose phosphates, glyceraldehyde 3-phosphate (GAP) and dihydroxyacetone phosphate (DHAP)
What does the second stage of glycolysis begin with?
-the cleavage of fructose-1,6-bisphosphate into two triose phosphates, GAP and DHAP
What is the problem associated with DHAP?
-dihydroxyacetone phosphate (DHAP) is not on the direct pathway of glycolysis, therefore the enzyme triphosphate isomerase, isomerizes the compound back to GAP
What is the initial reaction in stage 2 of glycolysis?
-the conversion of glyceraldehyde 3-phosphate into 1,3-bisphosphoglycoerate (1,3-BPG) which is an oxidation-reduction reaction catalyzed by glyceraldehyde 3-phosphate dehydrogenase
Which reaction of glycolysis is a redox reaction, and what type of bond does this reaction form?
-the conversion of GAP into 1,3-bisphosphoglycoerate and this forms a high energy bond which has a high phosphoryl transfer potential
The reaction catalyzed by glyceraldehyde-3-dehydrogenase can be viewed as the sum of what two processes?
1) the oxidation of the aldehyde, GAP to a carboxylic acid by NAD+
2) the joining of the carboxylic acid, 3-phoshpoglycerate and orthophosphate to form the acyl-phosphate product, 1,3-bisphosphoglycerate
What is the key intermediate for the coupling of oxidation to formation of an acyl anhydride in glyceraldehyde-3-phosphate dehydrogenase?
-the reactions are coupled by an intermediate that is linked to the enzyme by a thioester after the aldehyde has been oxidized
*a thioester intermediate
What is the role of phosphoglycerate kinase in stage 2 of glycolysis?
-phospoglycerate kinase transfers the acyl phosphate from 1,3-bisphosphoglycerate to ADP yielding ATP and 3-phosphoglycerate
What is the role of phosphoglycerate mutase?
-it is an enzyme that rearranges 3-phosphoglycerate into 2-phosphoglycerate, shifting the position of the phosphoryl group
What is the next reaction that occurs after 3-phosphoglycerate is made into 2-phosphoglycerate?
-the enzyme, enolase, catalyzes the dehydration of 2-phosphoglycerate and introduces a double bond, creating phosphoenolpyruvate
What is the role of pyruvate kinase?
-it is responsible for the irreversible transfer of a phosphoryl group from phosphoenolpyruvate to ATP
What are the net products of one molecule of glucose through glycolysis?
Why does glycolysis stop before long?
-because of a redox imbalance: all of the NAD+ has been consumed and made into NADH
What does ongoing glycolysis require?
-the regeneration of NAD+
What type of processes are fermentations?
-ATP generating processes in which organic compounds act as both donors and acceptors of electrons
What are the three possible fates of pyruvate?
-conversion into ethanol
-conversion into lactate
-conversion into acetyl CoA
How do many yeast and microorganisms regenerate NAD+?
-by reducing pyruvate to form ethanol through a process called alcoholic fermentation
-pyruvate is decarboxylated to acetaldehyde; this acetaldehyde is transformed into ethanol
-NAD+ is regenerated to be reused in glyceraldehyde phosphate dehydrogenase
How does lactic acid fermentation regenerate NAD+?
-the enzyme, lactate dehydrogenase, catalyzes pyruvate to accept electrons from NADH to form lactate
What does the regeneration of NAD+ in the reduction of pyruvate to lactate or ethanol sustain?
-the continued process of glycolysis under anaerobic conditions
What causes fatigue to set in, in a muscle that is functioning anaerobically?
-lactate builds up making it a more acidic environment
-the drop in pH may inhibit phosphofructokinase
Besides glucose, what other common carbohydrates can enter into glycolysis?
-fructose and galactose can be funneled into the glycolytic pathway
Why is excess fructose consumption a bad thing?
-fructose enters the glycolytic pathway in the liver through the fructose-1-phosphate pathway, and bypasses the most important regulatory step in glycolysis, the phosphofructose kinase-catalyzed reaction
-this leads to an unregulated production pyruvate and subsequently acetyl CoA; and this excess acetyl CoA is converted to fatty acids which be transported to adipose tissue resulting in obesity
What is the cause of lactose intolerance?
-the inability to metabolize milk sugar lactose due to a deficiency of the enzyme lactase, which is responsible for cleaving lactose into glucose and galactose
What is the cause of galactosemia?
-it is an inherited deficiency in galactose 1-phosphate uridyl transferase activity leading to an elevated blood-galactose level and galactose in the urine
What are the two major roles of glycolysis?
1) degrade glucose to generate ATP
2) provide building blocks for biosynthetic reactions, such as the formation of fatty acids and amino acids
What are potential sites of control in metabolic pathways?
-enzymes which catalyze irreversible reactions
What are the three regulation sites in glycolysis?
What is the primary control of glycolysis in the muscle cells?
-the energy charge of the cells, aka the ratio of ATP to AMP
When is glycolysis stimulated in the muscle cells?
-as the energy charge falls, it signals that the cell needs more ATP
What is the most important site of regulation of glycolysis in mammalian cells?
Why is AMP (not ADP) a positive effector of phosphofructokinase?
-AMP reverses the inhibitory effect of ATP by competing for binding sites of PFK, but when AMP is bound, it does not inhibit the enzyme
When does the activity of PFK increase (think about ATP/AMP ratio)?
-activity increases when the ATP/AMP concentration is lowered
What happens in a muscle cell when PFK is inactive?
-the concentration of fructose-6-phosphate rises and in turn the level of glucos-6-phosphate rises because it is in equilibrium with fructose-6-phosphate
What does the inhibition of PFK lead to?
-the inhibition of PFK leads to the inhibition of hexokinase
Why is PFK, not hexokinase, the main regulatory step enzyme in glycolysis?
-glucose-6-phosphate is not solely a glycolytic intermediate
-the first irreversible reaction unique to glycolysis is the phosphorylation of fructose-6-phosphate to fructose-1,6-bisphosphate
What is the allosteric inhibitor of pyruvate kinase in muscle?
-ATP allosterically inhibits pyruvate kinase to decrease the rate of glycolysis when the energy charge of the cell is high (product inhibition)
-when the pace of glycolysis increases, the product of the preceding irreversible step in glycolysis, fructose-1,6-bisphosphate, activates the kinase to enable it to keep pace with the oncoming high flux of intermediates
What is the physiological significance of the allosteric inhibitor of pyruvate kinase?
-At rest there is a high concentration of ATP that is not being used, therefore inhibiting PFK and pyruvate kinase, while glucose-6-phosphate inhibits hexokinase
What is the allosteric activator of pyruvate kinase in muscle?
-the decrease in AMP/ATP ratio resulting from muscle contraction which activates PFK and therefore, the rest of the glycolysis pathway
What is the physiological significance of the allosteric activator of pyruvate kinase?
-During exercise the muscle cell energy charge changes, decreasing the ratio of ATP to AMP, thereby activating PFK which is a feed forward stimulation that activates pyruvate kinase
Why is regulation of glycolysis more complex in the liver than in muscle?
-the liver has a greater diversity of biochemical functions than muscle
What is the liver's role in maintaining blood-glucose concentration?
-it stores glucose as glycogen, when glucose is plentiful
-releases glucose when supplies are low
In the liver, one major purpose of glycolysis is to make biosynthesis precursors, what molecule indicates that precursors are plentiful?
-a high level of citrate in the cytoplasm means that precursors are abundant, and so there is no need to degrade additional glucose for this purpose
What is phosphofructokinase inhibited by in the liver?
-citrate, which enhances the inhibitory effect of ATP on PFK
What is the key activator of PFK in the liver?
-fructose 2,6-bisphosphate (F-2,6-bP)
-this is the signal molecule through which the liver responds to changes in blood glucose
How does fructose-2,6-bisphosphate signal a large availability of glucose?
-after a meal rich in carbs, blood glucose concentration rises and the concentration of fructose-6-phosphate in the liver rises when blood-glucose concentration is high because of the action of hexokinase and phosphoglucose isomerase. The abundance of fructose-6-phosphate accelerates the synthesis of fructose-2,6-bisphosphate
What does the abundance of fructose-6-phosphate lead to?
-a higher concentration of fructose-2,6-bisphosphate
How does fructose-2,6-bisphosphate stimulate glycolysis?
-by increasing PFK's affinity for fructose-6-phosphate and diminishing the inhibitory effect of ATP on PFK
What is the important isozyme of hexokinase in the liver called?
-glucokinase, this enzyme is primarily responsible for phosphorylating glucose
What are isozymes or isoenzymes?
-enzymes encoded by different genes with different amino acids sequences, yet they catalyze the same reaction
-isozymes usually differ in kinetic or regulatory properties
In what conditions does glucokinase phosphorylate glucose?
-only when glucose is abundant, like after a meal, which allows the brain and muscle tissues the first chance to get glucose
What is different in terms of inhibition of glucokinase and hexokinase?
-glucokinase is not inhibited by its product, glucose-6-phosphate, but hexokinase is
-this means that the liver will continue to uptake glucose, even if it is already present at high concentrations in the liver
What does insulin signal?
-the need to remove glucose from the blood for storage as glycogen or conversion into fat
How does glucagon effect liver-pyruvate kinase?
-when the blood glucose concentration is low, the glucagon-triggered cyclic AMP cascade leads to the phosphorylation of pyruvate kinase, which diminishes its activity. This hormone triggered phosphorylation prevents the liver from consuming glucose when it is more urgently needed by the brain and muscle
What do the GLUT family of transporters do?
-mediate the thermodynamically downhill movement of glucose across the plasma membranes of animal cells
Which GLUT transporter only works at high concentrations of glucose?
-GLUT2 transporter, which is present in liver and pancreatic beta cells
-has a very high Km for glucose, therefore, glucose enters these tissues only when there is much glucose in the blood
What is the Warberg Effect?
-when rapidly growing tumor cells metabolize glucose to lactate even in the presence of oxygen
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