Carbohydrate Metabolism Flashcards
What is associated with deficiency of hexokinase?
Maturity onset diabetes of the youth
What converts fructose-6-phosphate in glycolysis?
Phosphofructokinase-2 and 1 (PFK) converts F6P to fructose-2,6-bisphosphate and fructose-1,6,bisphosphate, respectively
How does fructose-2,6-bisphosphate induce glycolysis?
By upregulating PFK-1
Citrate and ATP inhibit PFK-1
What endocrine signal upregulates PFK-2?
Insulin
PFK-2 converts F6P to F-2,6-bP
Glucagon decreases the concentration of ______
Glycolytic enzyme
F-2,6-bP, increasing activity of fructose-1,6-bisphophatase
Halts hepatic glycolysis and results in gluconeogensis
Decreased pyruvate kinase activity in RBCs
Equals decreased ATP, and hemolysis
Decreases the cells ability to pump cations against a concentration gradient
TCA cycle
What inhibits the first step of TCA cycle?
ATP inhibits citrate synthase
Elevated conc. of citrate blocks ______ ?
PFK-1 of glycolysis
Activates acteyl-coA-carboxylase of fatty acid synthesis
Isocitrate DH
Rate-limiting step
Requires Niacin
Produces CO2/NADH/alpha-ketoglutarate
Inhibited by ATP and NADH
Activated by ADP
Cofactors involved in alpha-ketoglutarate DH activity
Thiamine (B1)
Lipoic acid
CoA (B5, pantothenic acid)
FAD (vitamin B2, riboflavin)
NAD (B3, niacin)
“TLC for Nancy”
alpha-ketoglutarate DH
Converts alpha-ketoglutarate to succinyl-CoA
Produces NADH and CO2
Inhibited by ATP/NADH/Succinyl-CoA
Activated by Ca2+ in skeletal muscle
Wernicke-Korsakoff syndrome
Thiamine (B1) deficiency
sxs: ataxia, opthalmoglegia, and memory loss
Disorders related to thiamine deficiency
Dry-Beriberi
Wet-Berberi
Wernicke-Korsakoff
TCA cycle enzymes that require niacin (B3)
Isocitrate DH
alpha-ketoglutarate DH
Malate DH
NAD+ -> NADH (part of each of the above enzymatic processes)
What TCA cycle enzymes require riboflavin (B2)
alpha-ketoglutarate DH
Succinate DH (FADH2 to and from FAD)
What is complex II of the ETC?
Succinate DH
Also part of TCA cycle
Where does beta-oxidation and TCA cycle take place?
The mitochondria
The malate-aspartate shuttle
Reduction potential of the ETC complexes and carriers
When one oxygen molecule accepts electrons from the ETC, how many water molecules are produced?
Two H2O
How many total protons are pumped across the inner mitochondrial matrix when NADH+H+ reacts to with complex I to form NAD+?
Ten total H+’s are pumped
4 four complex I
2 from Q
2 from complex III
2 from complex IV
Becuase FADH2 reacts at complex II (which itself does not pump protons) only six protons are transferred as result
How many protons must transfer back through ATPase to generate one ATP?
Just over three protons
ATP equivalents of high-energy electron carriers produced by other metabolism?
Other than ETC
What toxic molecules bind to complex IV and prevent the reduction of O2 to H2O?
HCN/CO/N3
Biguanide
Metformin - selectively inhibits complex I of the ETC, leading to increased levels of ADP and AMP (AMP inhibits adenyl cyclase which produces cAMP)
cAMP inhibits adenyl cyclase - inhibiting gluconeogenesis and lowering blood glucose levels (acts as a glucagon antagonist)
Answer: B. Decreased ATP production in erythrocytes
Rationale: Pyruvate kinase deficiency results in reduced ATP production in erythrocytes. This leads to inadequate energy for maintaining the membrane cytoskeleton, resulting in hemolytic anemia. The characteristic spiculated red cells (echinocytes) are a result of this membrane instability.
Answer: C. Jejunoileal bypass surgery
Rationale: D-lactic acidosis is an unusual form of lactic acidosis caused by the accumulation of D-lactic acid in the colon due to bacterial carbohydrate metabolism. This condition is observed in patients with jejunoileal bypass or intestinal resection, which alters the gut microbiome and carbohydrate metabolism.
Answer: B. Inhibits phosphofructokinase-1
Rationale: Citrate is an allosteric inhibitor of phosphofructokinase-1 (PFK-1), a key regulatory enzyme in glycolysis. High levels of citrate indicate an abundance of biosynthetic precursors and energy, signaling a reduced need for glycolysis.
Answer: A. Decreased NADH oxidation in mitochondria
Rationale: The malate-aspartate shuttle is crucial for transferring reducing equivalents (electrons) from cytosolic NADH into the mitochondria. A defect in this shuttle would result in decreased NADH oxidation in mitochondria, leading to reduced ATP production through oxidative phosphorylation.
Answer: C. Glucokinase is primarily found in the liver
Rationale: Glucokinase (hexokinase IV) is primarily found in liver cells and has different kinetic properties compared to other hexokinase isoforms. It has a higher KM (lower affinity) for glucose, allowing it to respond to higher glucose concentrations and regulate glucose metabolism in the liver
Answer: C. Oxidative phosphorylation
Rationale: Leigh syndrome is a mitochondrial disorder characterized by progressive loss of mental and movement abilities. It typically results from mutations affecting oxidative phosphorylation, either in mitochondrial DNA or nuclear DNA encoding mitochondrial proteins
Answer: C. Inhibition of ATP synthase
Rationale: Oligomycin is an inhibitor of the F0 portion of ATP synthase. It blocks the channel through which protons flow back into the mitochondrial matrix, thereby inhibiting ATP synthesis. This leads to a buildup of the proton gradient and a decrease in ATP production through oxidative phosphorylation.
Answer: C. Used to reduce pyruvate to lactate
Rationale: In erythrocytes, which lack mitochondria, the NADH produced during glycolysis cannot be oxidized via the electron transport chain. Instead, it is used to reduce pyruvate to lactate via the enzyme lactate dehydrogenase. This regenerates NAD+ to allow glycolysis to continue, providing ATP for the erythrocyte
Answer: A. Decreased conversion of pyruvate to acetyl-CoA
Rationale: The pyruvate dehydrogenase (PDH) complex catalyzes the conversion of pyruvate to acetyl-CoA, which is the first committed step in aerobic metabolism. A mutation in this complex would lead to decreased conversion of pyruvate to acetyl-CoA, resulting in pyruvate accumulation and lactic acidosis.
Answer: B. Phosphofructokinase-1
Rationale: Phosphofructokinase-1 (PFK-1) is the main control point for glycolysis. Cancer cells often exhibit increased glycolysis rates (Warburg effect), and upregulation of PFK-1 would promote increased glucose utilization.
Answer: C. Decreased activity of pyruvate dehydrogenase complex
Rationale: Thiamine diphosphate is an essential coenzyme for the pyruvate dehydrogenase complex. Thiamine deficiency results in decreased PDH activity, leading to impaired pyruvate utilization and neurological symptoms due to inadequate energy production in neural tissues.
Answer: C. Increased glycolysis in cancer cells
Rationale: Cancer cells exhibit significantly increased rates of glycolysis, even in the presence of oxygen (Warburg effect). PET scans use radioactive glucose analogs, which accumulate in tissues with high glucose uptake and metabolism, making them effective for detecting cancer cells.
Answer: C. Inhibition of pyruvate dehydrogenase complex
Rationale: Arsenic poisoning results in the inactivation of the pyruvate dehydrogenase (PDH) complex due to irreversible binding of arsenates to the sulfhydryl groups of lipoic acid, a crucial component of the PDH complex. This inhibition blocks energy production through aerobic carbohydrate metabolism.
Answer: D. Activates phosphofructokinase-1
Rationale: AMP serves as an important allosteric activator of phosphofructokinase-1 (PFK-1). It is a more sensitive indicator of ATP consumption than ADP and effectively activates PFK-1 to increase glycolysis when energy levels are low
Answer: B. Decreased proton gradient across the inner mitochondrial membrane
Rationale: Complex III is crucial for electron transport and proton pumping across the inner mitochondrial membrane. A defect in Complex III would lead to a decreased proton gradient, impairing ATP production through oxidative phosphorylation.
Answer: B. Decrease proton gradient
Rationale: Uncoupling proteins, particularly UCP1 in brown adipose tissue, allow protons to leak across the inner mitochondrial membrane. This decreases the proton gradient, uncoupling electron transport from ATP production and dissipating energy as heat, a process important for thermogenesis.
Answer: C. Electron transport chain
Rationale: LHON is a mitochondrial disorder caused by mutations in mitochondrial DNA. These mutations typically affect complex I of the electron transport chain, leading to impaired oxidative phosphorylation and energy production, particularly affecting high-energy demand tissues like the optic nerve.
Answer: C. Glucokinase is primarily found in the liver
Rationale: Glucokinase (hexokinase IV) is primarily found in liver cells and has different kinetic properties compared to other hexokinase isoforms. It has a higher KM (lower affinity) for glucose, allowing it to respond to higher glucose concentrations and regulate glucose metabolism in the liver.
Answer: B. Activates α-ketoglutarate dehydrogenase
Rationale: ADP serves as an activator of several enzymes in the citric acid cycle, including α-ketoglutarate dehydrogenase. High levels of ADP indicate a need for increased energy production, stimulating the cycle to generate more reducing equivalents for ATP synthesis.
Kinetics of glucokinase vs. hexokinase
Hexokinase remains highly active even when glucose levels are low, ensuring the viability of glucose-dependent tissues.
Glukokinase allows rapid conversion to G6P when blood glucose is high, buffering blood glucose levels
Possible fates of G6P
Conversion to pyruvate (glycolysis)
Conversion to ribose-phosphate (pentoses, hexose monophosphate pathway)
Conversion to glycogen
Conversion to glucose (only in the liver, kidney, and intestines)
Synthesis of 2,3-bisphosphoglygerate
In erythrocytes, 1,3 BPG is converted to 2,3 BPG by BPG mutase.
Possible fate of pyruvate
Lactate DH - H isoform
Prominent in heart muscle
H isoform favors the conversion of lactate to pyruvate (found in lactate utilizing tissues such as the heart)
H4
Elevation of this form in serum indicates myocardial infarction since heart tissue damage releases this
Lactacte DH - M isoform
Prominent in skeletal muscle
The M isoform favors the conversion of pyruvate to lactate
M4 predominate form in skeletal muscle tissue
Under anaerobic conditions, _______ is produced
L-lactic acid
D-Lactic acidosis
Observed in patients with jejunoileal bypass or intestinal resection. Due to bacterial carbohydrate metabolism and accumulation of D-lactic acid in the colon.
Causes of lactic acidosis
Poor tissue oxygenation (inadequate circulation), diseased or compromised tissues (diabetes or malignancy) or drugs/toxins that interfere with oxidative metabolism.
Pyruvate kinase inhibition (liver isoform)
Inhibited by ATP, acetyl CoA, and fatty acids. Helps regulate energy utilization and the TCA cycle when energy stores are high and the cycle is slow.
PFK regulation
AMP is more sensitive allosteric activator than ADP - displaces ATP (allosteric inhibitor)
Citrate - another allosteric inhibitor
The TCA cycle represents the convergence of the metabolism of what macromolecules?
Carbohydrates/fats/proteins
Where is PDH?
Pyruvate DH complex is in the mitochondria (pyruvate has to be transported in from the cytosol)
Regulated steps of TCA cycle
Citrate synthase
Isocitrate DH
Alpha-ketoglutarate DH
Citrate synthase
Isocitrate DH
Alpha-ketoglutarate DH
Succinate DH
AKA complex II of ETC
Malate DH
Net reaction of TCA cycle
TCA cycle’s role in lipid synthesis
Acetyl-CoA is the primary source of carbons for fatty acids and cholesterol.
Citrate also serves as a source of acetyl-CoA.
Acetyl-CoA cannot pass across the inner mitochondrial membrane, and citrate serves as mechanism to transport acetyl-CoA out of the mitochondria, where it is metabolized using the enzyme ATP citrate lyase.
Major metabolic controls of TCA cycle
Galactose metabolism
What converts galactose-1-phosphate to glucose-1-phosphate?
Galactose-1-phosphate uridyltransferase
Deficiency - classic galactosemia
galactose-1-phosphate is toxic - builup in liver - damage
Also, cataracts
Susceptible to sepsis with E. coli infections
Fructose metabolism
Underline - where enters glycolysis
Hereditary fructose intolerance
Dysfunction of aldolase-B
More serious than essential fructuria - fructose-1-phosphate is trapped in the cell
Deficiency of the enzyme aldolase-B - ATP is wasted by producing fructose-1-phosphate (cannot be utilized)
*New food
Polyol pathway
Increased levels of sorbitol (due to hyperglycemia) - osmotic damage - cataracts
ETC inhibitors/disruptors
Rotenone is more important than amytal
Pentose phosphate pathway
Aka hexose monophosphate shunt
PPP - oxidative pathway
PPP - Non-oxidative pathway
Transketolase - key enzyme in non-oxidative branch (requires thiamine pyrophosphate - TPP)
Pyruvate DH complex
Rotenone (Amytal is stronger inhibitor = sicker Pt)
Which of the following conditions is characterized by the presence of fructose in the urine?
Essential fructosuria
Classical galactesemia
Glycogen phosphorylase
Hydrolyzes residues from the nonreducing ends through phosphorolysis. The enzyme will not cleave beyond four residues from a branch.
Active when phosphorylated (muscle)
Glucan transferase
A debranching enzyme. Glucan transferase moves three residues from a branch to the main chain.
α(1→6) glucosidase
aka debranching enzyme
Another debranching enzymes. α(1→6) glucosidase removes the remaining glucose residue (steps two and three are two activities of the same enzyme)
Glycogenin
Protein that serves as primer for glycogen synthesis. Catalyzes the transfer of a glucose from UDP-glucose to the hydroxyl group of a Tyr residue on the protein. The chain is extended, eventually becoming a substrate for glycogen.
Glycogenin remains buried in the core of the glycogen molecule
Comparison of glycogen metabolism in muscle vs liver
Von Gierke (type I) disease
Due to a deficiency in glucose-6-phosphatase, which is needed for the release of glucose produced from either gluconeogenesis or glycogen. Results in severe fasting hypoglycemia. It causes hepatomegaly due to the accumulation of glycogen stores in the kidney and liver.
Pompe’s disease (type II)
Due to a defect in a lysosomal enzyme, lysosomal acid glucosidase, that is responsible for the turnover of glycogen particles. It acts similarly to maltase in the digestive tract but functions in lysosomes and is sometimes referred to as acid maltase.
It results in severe cardiac and skeletal muscle myopathy.
Cori’s disease
Due to a loss of the debranching enzyme and results in glycogen accumulation in muscle and fasting hypoglycemia.
McArdle disease
Due to a deficiency in muscle glycogen phosphorylase. Primary sx is cramping, muscle pain, and myoglobinuria following exercise.
Metabolism of alcohol
Pathway
The activity of what enzyme is upregulated in Pt’s w/ essential fructosuria?
Patients with essential fructosuria have fructokinase deficiency and thus cannot convert fructose to fructose-1-phosphate. Hexokinase (found in adipocytes and myocytes) becomes the primary enzyme responsible for fructose metabolism and converts it to fructose-6-phosphate, which can be used for glycolysis or converted to glucose-6-phosphate by glucose-6-phosphate isomerase. Fructose that is not converted by hexokinase is excreted in urine, which leads to the presence of reducing substances.
AMBOSS
