Interconversion of Glucose and Other Sugars
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- What is the key site (pathway) for NADPH and ribose-5-phosphate synthesis?
- PPP
- Why are reducing equivalents produced in PPP important to RBCs?
- they defend against O2 toxicity
- What is the PPP also referred to as?
- the hexose monophosphate shunt
- Is the PPP unidirectional?
- no, 5 -> 6 and back again
- What other positive aspects are there in th PPP?
- reducing equivalents (NADPH)
- What two things make NADPH production a good thing?
- a) biosynthesis of fatty acids b) prevent oxidative damage
- What role does NADPH drug detoxification?
- NADPH is required in drug detoxification
- Are ingested alternate sugars used in the glycolytic pathways?
- No, they are broken down. If needed they are resynthesized from glucose.
- How can galactose enter the glycolytic pathway?
- converted to glycogen or G-1-P (which can be converted to G-6-P)
- PPP occur in tissue that require high amounts of reducing equivalents (NADPH), which three organs are these?
- liver, mammary glands, the adrenal cortex
- What perctage of glucose oxidation is done by PPP in adipose tissue? Why is this percentage so high?
- a) 50% b) fatty acid biosynthesis occurs there
- What is the first stage of the PPP?
- Oxidative
- Which branch of the PPP produces reducing equivalents?
- the first (oxidative)
- Is the oxidative rxn of the PPP revesible?
- No
- What happens in the first branch of the PPP?
- G-6-P is converted to ribulose-5-phosphate
- What does the non-oxidative branch of the pathway do?
- Converts pentose sugars back into 6 carbon sugars
- Is the non-oxidative branch of the PPP reversible?
- yes
- What is glucose-6-phosphate dehydrognenase? How is it inhibited?
- It converts G-6-P to Ribulose-5-P in the oxidative part of the PPP... b) Feedback (product) Excess NADPH
- What is the branch point for the oxidative part of the PPP?
- G-6-P
- What inhibits oxidative PPP branch?
- product inhibition (NADPH)
- What effect does a high insulin to glucagon ratio have on the oxidative branch of the PPP?
- positive regulation
- What effect does a high insulin to glucagon ratio have on G-6-P dehydrogenase? And it's Vmax?
- a) increases synthesis b) increased Vmax (its capacity)
- Where is the gene for G-6-P dehydrogenase, which plays a key role in PPP?
- X-chromosome
- When would an individual with a defect in G6PD experience difficulty?
- during oxidative stress, since defects in G6PD are sensitive to oxidants
- What is one clinical manifestation of a defect in G6PD?
- hemolytic anemia due to RBC destruction
- Do most mutation in G6PD cause symptoms?
- No
- What is the biochemical reason for the vulnerability of G6PD deficient individuals?
- G6PD (defective) > no NADPH > no reduction of Glutathione thus it cannot cycle between reductase and peroxidase forms > no removal of reactive oxygen species (ROS produced in healthy individuals too), nor hydrogen and lipid peroxides.
- Which form of glutathione deals with radicals?
- glutathione peroxidase
- What food can cause oxidative stress?
- fava beans
- What do oxidants cause?
- crosslinking of hemoglobin, called Heinz bodies, which can cause cell lysing and difficulty passing through capilaries
- Which branch of the PPP is referred to as the transketolase reaction?
- non-oxidative
- What are the 5-carbon sugars converted to in the transketolase reaction?
- F-6-P and Glyceraldehyde-3-P
- What do the transketolase reaction, pyruvate dehydrogenase reaction, and the ∂-ketoglutarate dehydrogenase reactions require?
- Thiamine pyrophosphate as a cofactor
- What is good way to assess a thiamine deficiency?
- check transketolase activity
- What is thiamine deficiency associated with?
- alcohol consumption
- Because thiamine is turned over quickly how do deficiencies present?
- short periods of time over several weeks
- What are the short term symptoms of thiamine deficiency?
- appetite loss, nausea, depression, and fatigue over a short period of time.
- What are the chronic symptoms of thiamine deficiency?
- mental confusion, unsteadiness, loss of eye coordination and congestive heart failure (Wernicke-Korsakoff syndrome)
- Which measurement can be used to diagnose thiamine deficiency?
- Transketolase
- What does a severe deficiency of thiamine cause and what is it known as?
- Beriberi, neuromuscular symptoms, including muscular atrophy and weakness.
- What is the significance of UDP Glucose? How is it formed?
- a) Its an activated sugar with a higher energy level, b) it is formed by the
- What must happen to the glucose prior to conversion to lactose?
- It must first be converted to a higher energy state call UDP-galactose
- Which enzyme converts UDP-glucose to UDP-galactose?
- Epimerase
- What is the linkage configuration of lactose?
- ß-1-4 linkage
- What is the enzyme that converts UDP-galactose to Lactose?
- Lactose synthase (works with ∂-lactalbumin)
- What is alpha lactalbumin?
- a protein that is released after childbirth, in response to prolactin, that modulates the Km by about 1000 times
- In the fructose pathway, what is the first step and which enzyme catatlyzes this step?
- Fructose to F-1-P, fructokinase
- What are the second and third steps in the fructose pathway? And what is the enzyme that catalyzes this process?
- a) F-1-P to dehhydroxyacetone-P to glyceraldehyde-3-P (or vice versa), b) aldolase-B, c) triose kinase
- Which enzyme toggle between dehhydroxyacetone-P and glyceraldehyde-3-P
- triose kinase
- Besides F-1-P, which other substrate can aldolase B (in the liver) metabolize?
- F-1,6-BisP
- Which substrate does aldolase have a lower Km, F-1-P or F-1,6-BisP?
- F-1,6-BisP
- What is the rate limiting step in fructose metabolism?
- F-1-P to dehhydroxyacetone-P or glyceraldehyde-3-P
- In terms of enzymes, why will fructose-1,6-BisP only be metabolized in the liver?
- Aldolase-A, found in the muscle, can only metabolize F-1,6-BisP, while the liver can also metabolize F-1-P
- What are the adverse effects of a fructokinase deficiency?
- none⬦ it's benign⬦ fructose is just excreted
- What are the adverse effects of a deficiency in aldolase B?
- the accumulation of F-1-P inhibits glycogenolysis and gluconeogenesis
- What pH imbalance does the inhibition of gluconeogenesis cause?
- lactic acidosis
- What function does aldolase B serve in Glucose synthesis?
- it synthesizes glucose from G-3-P and DHAP
- What effect does F-1-P have on aldolase, with respect to glucose synthesis
- it depresses aldolase B already low activity
- What effect does the accumulation F-1-P have on cellular phospate?
- it depletes cellular phosphate, due to rapid ATP hydrolysis of fructokinase.
- What effect does low phosphate have on cells?
- low phosphate activate AMP deaminase⬦ amp-> IMP-> uric acid, which leads to depletion of adenine nucleotides⬦ thus ATP synthesis is limited
- What are the two steps in galactose metabolism that leads to the glucose-1-P and ultimately G-6-P? and their enzymes?
- a) Galactose to galactose-1-P (enzyme is galactokinase + ATP) and b) Galactose-1-P to glucose-1-P (enzyme = uridylytransferase also known as GALT)
- In the second step of galactose metabolism how do you derive G-1-P?
- galactose-1-P + UDP glucose -> G-1-P + UDP galactose
- What role does epimerase play?
- UDP galactose -> UDP glucose
- In general which is more serious galactose enzyme deficiencies or frutose deficiencies?
- Galactose, but the scheme is the same, i.e., GALT is worse than galactokinase.
- Which part of galactose metabolism is a deficiency referred to as non-classical? Which is classical?
- a) non-classical deficiency is part one, which involves galacokinase⬦ b) classical deficiency is part two which involves GALT
- How do you treat non-classcal deficency?
- remove galactose and lactose (lactose = glucose and galactose)
- What is a consequence of galactosemia? How does this occur?
- Juvinile cataracts⬦ b) via conversion of galactose to galactitol via aldose reductase in polyol pathway.
- Why does galactitol only occur when galactose is actually ingested?
- Because Km for aldose reductase is high and thus affinity is low, unless galactose is in high quantity.
- What is the problem with the GALT deficiency?
- Galactose-1-P is an inhibitor of UDP-glucose pyrophosphorylase, which is a key enzyme in the breakdown of glycogen
- What are the manifestations of a GALT deficiency?
- failure to thrive, mental retardation, jaundice and liver disease
- How is GALT activity measured?
- blood test