Week 6: Urea Cycle, Metabolic Priorities, and Diabetes Flashcards
Describe and/or draw the reactions that form urea, and explain where in the cell they occur.
(1) In the mitochondria, ornithine is added to carbamoyl phosphate (a pyrimidine synthesis intermediate) to form citrulline
(2) Citrulline leaves the mitochondria, entering the cytosol. It adds aspartate (an AA), forming Argininosuccinate.
(3) Fumarate is cleaved, forming arginine
(4) Urea is hydrolyzed, forming ornithine
(5) Ornithine enters the mitosol to bind another carbamoyl phosphate and restart the cycle
What are key aspects of the urea cycle as it relates especially to protein?
(1) Aspartate is used to transfer an NH3 group
(2) Arginine, a glucogenic AA is used in the process
(3) Ornithine can be formed from arginine AND glutamate
(4) Glutamate will be limiting if [TCAI] is low (stuck in interconversion with a-ketoglutarate), and would be very low if AAs become limiting
(5) The urea cycle WILL NOT happen if [AAs] is low to save protein
What links the urea and TCA cycles?
Asparatate is used to abstract an NH3 from glutamate, reforming a-ketoglutarate which can reenter the TCA cycle. Aspartate will be added to citrulline to form argininosuccinate in the urea cycle. Further, fumarate is formed when argininosuccinate is cleaved to form arginine, and fumarate can re-join the TCA cycle after conversion to malate to cross back into the mitochondria.
The formation of carbamoyl phosphate requires 2 ATP molecules. It also helps regenerate NADH from NAD+. Explain the process of moving from glutamine and glutamate to carbamoyl phosphate, and why it is energetically favorable.
Though the process costs 2 ATP molecules, it generates 5 as well, netting 3 ATP overall. Glutamine and glutamate enter the liver mitochondria, where they are transformed to a-ketoglutarate, a TCA cycle intermediate, by removal of nitrogens from glutaminase (glutamine to glutamate) and glutamate dehydrogenase (glutamate to a-ketoglutarate). The addition of this first ammonia (NH4) group to bicarbonate (HCO3-) costs 2 ATP, but generates 2 NADH in the process. Each NADH can move to the ETC, pump 20 protons total (1 ATP/4H+) and generate 5 ATP.
How is glycerol converted to GAP/G3P?
(1) Glycerol kinase converts glycerol to glycerol-3-phosphate
(2) Glycerol phosphate dehydrogenase generages dihydroxyacetone phosphate (DHAP)
(3) Triose phosphate isomerase converts DHAP to GAP/Glyceraldehyde 3-phosphate
How does the body shift away from the use of protein to make TCAIs to other sources?
FA oxidation to AcCoA and ketone bodies are used primarily, though only some tissues can use them–these include the heart, brain, and muscle
Describe the first and second major metabolic priorities of the body
First priority: provide glucose to the brain and RBCs
Second priority: preserve protein
What molecules help dictate metabolic priority, and how?
High catecholamines and low insulin help carry out these priorities. Low insulin prevents the muscle and fat cells from taking up glucose, and catecholamines stimulate FA mobilization to the liver, where liver enzymes produce high volumes of ketone bodies
Starting with protein degradation, explain how glucose export to the brain is prioritized.
(1) Protein degradation yields glucogenic amino acids. This forms urea in the process, which is moved to the kidneys and excreted.
(2) OAA is converted to PEP, which is then used in the reverse process of glycolysis to form glucose. Glucose is exported to the brain via the bloodstream.
After gluconeogenesis begins to export glucose to the brain, what occurs in other cells to shift metabolic priority?
(1) FA are oxidized as fuel in other tissues (any that have mitochondria, so not RBCs), producing AcCoA
(2) AcCoA accumulates in the liver cells to generate OAA–without other TCAIs, however, low OAA prevents AcCoA from entering the TCA cycle
(3) AcCoA accumulation favors ketone body synthesis
(4) ketone bodies are formed from FAs in the liver from FA oxidation. They are then exported to the brain and muscle, which can use them as fuel.
What is diabetes mellitus and how is it characterized?
It is a group of diseases affecting glucose homeostasis, all of which are characterized by hyperglycemia. This happens for two reasons. In Type I DM, an autoimmune disorder prevents the b-cells of the pancreas from secreting insulin, so cells will not take in glucose. In Type II DM, overproduction of insulin made cells insensitive over time, and exhausts the b-cell insulin production capacity. Thus, low insulin is produced by these cells. Either way, this induces the body’s tissues to undergo gluconeogenesis in an attempt to “restore” glucose delivery to body tissues, even though there is plenty available.
It usually involves insulin deficiency or dysfunction on target tissues. Life-threatening symptoms include ketoacidosis (low blood pH, <7.35) and hyperosmolar hyperglycemic nonketotic coma (VERY high blood volume/low cell volume as fluid is pulled out of cells to balance high osmolarity of blood due to sugar)
What is leptin and the lipostat theory? What is the phenotype of leptin knockout mice?
Leptin is a signaling molecule sent from adipose tissue that establishes a set-point for optimal fuel metabolism and the maintenance of a constant mass. Defects in leptin-encoding genes produces:
Behavior consistent with a constant state of starvation
Inability to stay warm
Sterility
Elevated cortisol levels
Insulin resistance
What is adiponectin and how does it play a role in metabolic balance
Adiponectin is a signaling molecule that shifts metabolism toward FA oxid. and away from FA/glucose synthesis. Mice with defective adiponectin genes are less sensitive to insulin, and display metabolic defects similar to those of Type II diabetes.
Explain how adipose tissue itself helps regulate metabolism and fatty acid oxidation
The formation of adipose tissue generates leptin, which suppresses appetite and stimulates FA oxidation as opposed to FA synthesis. This creates energy and heat, and burns fat! Knocking out the leptin gene (ob/ob mice) conferred individuals that were unable to stay warm, had an unrestrained appetite, and insulin resistance.
How does leptin act in the brain to downregulate sensations of hunger?
It signals to the hypothalamus that the body is in a satiated state, which creates a sympathetic response lowering the desire to be a total fatass
How does norepinephrine affect adipocytes?
It activates PKA through a GCPR and increases expression of uncoupling protein in mitochondria. As FAs are released from these cells, b-oxidation occurs in the mitochondria and generates heat instead of ATP–this is how we stay fit, fam!
What effects does leptin have on insulin cell signaling?
(1) Leptin receptors, when activated, phosphorylates the same protein as the RTK receptors of insulin. The proteins are thus more easily activated in the second messenger pathway, making the cell more sensitive to insulin.
(2) It also activates AMP-dependent protein kinase (AMPK), which minimizes energy expenditure from glucose while maximizing the use of energy reserves like FAs when available
