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71 Cards in this Set

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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