Carbohydrate Metabolism - NYIT Flashcards
How does arsenic poison/harm?
Arsenic in the form of arsenate looks like phosphate in structure, it adds to glyceraldehyde-3-P in step 6. It causes instability and spontaneous hydrolysis of G3P -> 3-phosphoglycerate bypassing the substrate level phosphorylation and preventing the net 2 ATP from forming.
particularly damaging to RBC because glycolysis is their one form of energy production
how does flouride work?
inhibits enolase at step 9 and the production of phosphoenolpyruvate
pyruvate kinase deficiency
recessive mutation causes RBC to express markedly lower levels of pyruvate kinase and because RBC lack mitochondria this effects their source of energyand the produce 50% ATP leading to hemolytic anemia
what tissues produce lactate normally? what causes lactate production over Acetyl-CoA?
RBCs, Skin, Brain, Skeletal muscles and renal medulla
In times lacking of mitochondria and in times of low oxygen
What’s the cori cycle? What tissues use it?
cori cycle is the generation of lactate in either skeletal muscle during extreme exercise or RBC. Lactate is produces for the reoxidizing of NADH to NAD+. When at rest the lactic acid travels by blood to the liver where it’s converted to glucose by gluconeogensis.
RBCs only use this cycle because of no mito
lactic acidosis
caused by elevated plasma concentration of lactate which decreases pH
can be caused by failure to re-oxidize NADH (maybe by a blocked ETC), ethanol intoxication (excess NADH), pyruvate carboxylate deficiency, impaired PDH, respiration or oxygen delivery (like CO poisoning) or excessive exercise
glucogon causes what metabolism changes?
inc glycogenolysis
inc gluconeogenesis
inc lipolysis
dec liver glycolysis
activates protein kinase A
insulin causes what metabolism changes?
inc glycogen synthesis
inc fatty acid synthesis
inc triglyceride synthesis
inc liver glycolysis
activates phophatase
Pyruvate Dehydrogenase Complex
alpha-keto acid dehydrogenase family of enzymes
Contains 3 subunits: E1, E2, E3
E1 - thiamine/TPP coenzyme
E2- lipoic acid and Coenzyme A
E3 - FAD+ and NAD+
converts pyruvate to acetyl-coa with release of CO2 and NADH per pyruvate
How is PDH regulated?
turned on by PDH phosphatase and off by PDH kinase
Kinase in inhibited by pyruvate and ADP and activated by acetyl-coa and NADH
phosphatase is activated by Ca2+
What are the irreversible steps of that CAC?
Step 1 - citrate synthase formation of citrate from acetyl-coa and oxaloacetate.
step 3 - isocitrate dehydrogenase (Rate Limiting) and forms alpha-ketogluterate. Produces CO2 and NADH and H+
What inhibits citrate synthase?
citrate, NADH, succinyl-CoA
what step of CAC is inhibited by flouroacetate? (rat poison)
aconitase - enzyme for isomerization of citrate - step 2
what regulates the rate limiting step of the Krebs cycle?
isocitrate dehydrogenase is inhibited by ATP and NADH and activated by Ca2+ and ADP
isocitrate -> alpha-ketogluterate
whats the second step of CAC that releases CO2?
step 4 that is catalyzed by alpha-ketogluterate dehydrogenase and produces succinyl CoA
Release CO2, NADH and H+
product has a high-energy bond
inhibited by high energy products and activated by Ca+
what step of the TCA Cycle produces ATP?
Indirectly by way of GTP, the high energy bond from succyinl CoA gets transferred to succinate by succinyl-coa synthetase making a GTP which transfers to make a ATP - step 5
what’s unique about succinate dehydrogenase?
It also serves as complex II of the ETC, ONLY ENZYME OF THE CAC EMBEDDED IN THE INNER MITO MEMBRANE
In step 6 of the CAC is catalyzes the rxn succinate -> fumerate releasing FADH2
what is the purpose of malate dehydrogenase?
malate dehydrogenase is step 8 of the CAC and it regenerates oxolaacetate and releases the final NADH
whats the total amount of ATP that can be produced out of glycolysis, PDH, CAC and ETC?
36 to 38 ATPs
what are the 3 most important regulated enzymes of the CAC?
citrate synthase (-) citrate isocitrate dehydrogenase (+) ADP, Ca2+. (-) NADH alpha-ketogluterate dehydrogenase (+) Ca2+. (-) NADH
what is a way that oxaloacetate can be replinished in the CAC cycle?
pyruvate carboxylase converts pyruvate to oxaloacetate
cofactor - biotin and requires ATP/Mg2+
(+) Acetyl-CoA
Also, first enxzyme of gluconeogenesis
what is an anaplerotic reaction?
rxns that replinish intermediates of the TCA cycle (anaplerotic means filling up)
done form amino acid degradation
what are Leigh syndromes?
subacute necrotizing encephalomyelopathy
caused by one of many mutations, PDH complex deficiency and pyruvate carboxylase deficiency are two of them
causes lactic acidemia, which leads neurologic damage, and u
Beriberi disease or Wernicke-korsakoff syndrome
thiamine Vit B1 def, a cofactor of PDH and alpha-ketogluterate dehydrogenase
how does insulin effect Fructose 2,6- Bisphosphate levels?
Insulin activates the phosphatase which will in turn de-phosphorylate PFK-2 (activating it’s kinase abilities) the PFK-2 kinase phosphorylates Fructose-6-Phosphate to F-2,6-BisP, which in turn activates PFK1 at step 3 of glycolysis
opposite happens for glucogon which activates the phosphatase ability of PFK2 and dephos F2,6BP to F6P
PFK2 is active with dephos
what is the activator of glycolysis?
Fructose-2,6-BisPhosphate
what is the purpose of gluconeogenesis and where does it happen?
it’s purpose is for glucose homeostasis as tissues like RBC can only use glucose and the brain who perfers use of glucose
happens in the liver, somewhat kidney
what are the precursors that can feed into gluconeogensis?>
lactate
pyruvate
alanine by removal of amino group (alpha-ketoacid),
-> pyruvate from muscle gets converted to alanine which transports to liver, alanine will drop off the amino to the urea cycle in the liver and then provide pyruvate for gluconeogenesis (glucose-alanine cycle)
glycerol (from fatty acid breakdown) - enters as DHAP with Glycerol 3 phos intermediate
what enxyme reverses step 10 of glycolysis and serves as step 1 of gluconeogenesis?
pyruvate -> oxaloacetate by pyruvate carboxylase (biotin cofactor)
irreversible, activated by Acetyl-CoA
in mitohondria
what is the significance of step 2 of gluconeogenesis?
by PEP carboxykinase the reversing of step 10 of glycolysis is complete and oxaloacetate is converted to PEP, this requires GTP
irreversible
starts in mitochondria and moves to cytosol
3rd reaction of gluconeogenesis that reverses a step of glycolysis?
reversal of step 3 of glycolysis, dephosphorylation of Fructose 1,6-BisP to F-6-P by Fructose I,6-BisPhosphatase
irreversible and inhibited by F-2,6-BP and AMP
what’s the final step of gluconeogenesis that reverses the first step of glycolysis?
Glucose-6-Phosphate to Glucose by Glucose-6-Phosphatase, irreversible, enzyme found in ER membrane and only in the liver and kidney
how much energy is consumed by gluconeogenesis?
where does this energy come from?
6 ATP and 2 NADH
fatty acid breakdown
regulation of gluconeogenesis
signal for activation: during fasting or prolonged exercise, with a high protein diet or during stress or injury
when it’s subtrates are available and NAD+
alcohol -> impairs gluconeogenesis causing low blood sugar and high lactose (acidosis)
glucogon - activates
pentose phosphate pathway, what goes in and what goes out?
Glucose-6-phosphate goes in the oxidative path releasing a C02 and producing NADPH and/or 5C-sugar - irreversible
Fructose-6-phosphate enters non-oxidatively producing ribose-5-phosphate and bypassing NADPH production - reversible
enzymes are G6PDH - oxidation. transketolase and transaldolase are non-oxidative
Uses of NADPH?
biosynthesis
reduction of glutathione for dealing with ROS
reduction of oxygen to produce ROS
what combinations of products are available from the pentose phosphate pathway?
NADPH x2 NADPH and Ribose-5-phosphate ^oxidative and irreversible ribose-5-phosphate only ribose-5-phosphate and ATP ^non-oxidative and reversible
Glucose-6-phosphate dehydrogenase def
G6PD or G6PDH deficiency - mutation that causes a decrease in activity
without NADPH for RBC the concentration of ROS rises and damages Hb, Hb forms crosslinked aggregates called Heinz bodies on the cell membrane which compromises its integrity causing hemolysis as the RBC tries to travel into small capillaries
NADPH makes reduced glutathione which removes H2O2 and lipid peroxides
what color does glycogen stain with what type of stain?
magenta with PAS stain
where in the body and where in the cell is glycogen stored?
in liver, skeletal muscle and kidney
in cytosol as granules
at what point of glycogen are free glucose added?
the non-reducing end - the end without a free aldehyde
what type of linkages do you find in glycogen?
alpha-1,4 linkages
alpha-1,6 linkages - branching (branching occurs every 8 to 12 residues)
Glucose-6-Phosphate enters glycogenesis as what form?
glucose-1-phosphate
how does glucose get added to the non-reducing end of glycogen?
it’s carried by UDP-Glucose, glycogen synthase catalyzed the transfer from UDP to the chain
what step of glycogenesis is irreversible?
the activation of G1P to UDP-glucose giving a PPi, by UDP-glucose pyrophosphorylase
glycogen synthase addition to non-reducing end with 1,4 linkages is also irreversible
what’s a requirement of glycogen synthase thats similar to DNA replication?
requires a primer, oligosaccharide primer
primer is made by glycogenin (both a enzyme and scaffold) builds a oligomer using UDP-glucose as donors (8)
First glucose is added to tyrosine residue
the only reducing end is found on the glucose linked to glycogenin
branching in glycogenesis
branching enzyme - 1,4 to 1,6 transferase removes 6 to 8 residues from the non-reducing end of glycogen and attaches it about 4 residues away from the last branch as a 1,6-glycosidic linkage
glycogenolysis
done by glycogen phosphorylase which is irreversible and regulated. Removes alpha-1,4-linkages using P (traveling on pyridoxyl phosphate with Vit B)
debranching enzyme
bifunctional protein
4:4 glucan transferase removes 3 glucose to the nonreducing end. leaving single alpha-1,6-linkage which is removed by alpha-1,6-glucosidase releasing a free glucose at the branching point as G-1-P
exact location of glucose-6-phosphatase
ER of liver cells
pompe disease
type II glycogen storage disease
deficiency of lysomal alpha-1,4-glucosidase causing accumulation of glycogen
inborn
excessive glycogen in lysosomes
enlarged heart
infantile onset -> early death from heart failure
effect of phosphorylation on glycogen synthase and phosphorylase
phosphorylation turns off glycogen synthase and turns on glycogen phosphorylase (through phosphorylase kinase) glucogon stimulates phosphorylation
insulin causes dephosphorylation which turns on glycogen synthase and off GP
allosteric regulators of glycogenesis and glycogenelysis
allosteric inhibitors of glycogonolysis - G-6-P, ATP and Glucose in liver,
AMP is a positive regulator in muscle
glucose-6-phosphate positively regulates both tissues in glycogenesis
what tissue does glucogon not effect? What tissue is AMP effective in?
glucogon has no effect in muscle
AMP is in the muscle, has no effect in liver
von gierke disease type Ia and type Ib
Type Ia - glucose-6-phosphatae
Type Ib - glucose-6-phosphate translocase - neutropenia and recurrent infections
fasting hypoglycemia, liver and kidney, fatty liver and hepato- and renomegaly, growth retardation and delayed puberty, increased glycogen storage, progressive renal disease
treatment - nocturnal infusions of glucose
cori disease
4:4 transferase or 1:6 glucosidase def
causes fasting hyprglycemia and glycogen has an abnormal structure
McArdle syndrome
skeletal muscle glycogen phosphorylase def
liver enzyme is normal, temporary weakness and cramping of skeletal muscle after exercise, no rise in lactate during strenuous exercise, myoglobinemia and myoglobinuria, benign but chronic, lots of glycogen in muscle
def in liver enzyme causes Type VI hers disease
Fructose metabolism
main source is sucrose and fruits/veggies
transporter is GLUT5
enzymes are fructokinase and aldolase B
fructokinase def
essential fructosuria is autosomal recessive, benign and causes fructose accumulation in the blood
hereditary fructose intolerance
aldolase B def
autosomal recessive
causes severe hypoglycemia, vomiting, jaundice, hemorrhage, hepatomegaly, renal dysfunction, hyperuricemia and lacticacidemia
sorbital metabolism
alcohol of glucose
enzymes are aldose reductase and sorbital dehydrogenase
hyperglycemia causing sorbital accumulation cataract formation, peripheral nephropathy or retinopathy
galactose metabolism
from lactose
galactokinase phosphorylated galactose, galactose-1-phosphaste UT activates galactose-P and, UDP-hexose 4-epimerase converts it to UDP-Glucose which leaves as G-1-P
galactokinase def
rare, autosomal recessive
elevation of galactose in blood and urine
galactitol accumulation -> cataracts
treatment is dietary restriction
classic galactosemia
galactose 1-phosphate uridylytransferase def
autosomal recessive
galactosemia and galactosuria, vomiting, diarrhea and jaundice
accumulation of galactose-1-phosphate and galacititol in nerve, lens, liver and kidney
developmental delay
early ovarian failure in women
aldose reductase
unimportant unless galactose levels are high
elevated galactitol -> cataracts
what two enzymes release free glucose?
glucose-6-phosphatase
alpha-1,6-glucosidase (debranching)
