Hormones & Integrated Metabolism

·         Type I hormones like the steroid hormones, including the sex hormones estrogen, testosterone, and progesterone are lipophilic, allowing them to diffuse into the cytosol, form ligand-receptor complexes, and mediate action in the cytosol or nucleus. Type II hormones like epinephrine interact with membrane receptors, often activating G protein complexes, elevating cytosolic levels of adenosine 3′,5′-cyclic monophosphate (cyclic AMP), and modifying protein kinases.

·         Digitalis and ouabain are cardiotonic steroids that inhibit the Na+,K+-ATPase pump located in the plasma membrane of cardiac muscle cells. They specifically inhibit the dephosphorylation reaction of the ATPase when the cardiotonic steroid is bound to the extracellular face of the membrane. Because of inhibition of the pump, higher levels of sodium are left inside the cell, leading to a diminished sodium gradient. This results in a slower exchange of calcium by the sodium-calcium exchanger. Subsequently, intracellular levels of calcium are maintained at a higher level and greatly enhance the force of contraction of cardiac muscle.

·         Leukotrienes C4, D4, and E4 together compose the slow-reacting substance of anaphylaxis (SRS-A), which is thought to be the cause of asphyxiation in individuals not treated rapidly enough following an anaphylactic shock. SRS-A is up to 1000 times more effective than histamines in causing bronchial muscle constriction. Anti-inflammatory steroids are usually given intravenously to end chronic bronchoconstriction and hypotension following a shock. The steroids block phospholipase A2 action, preventing the synthesis of leukotrienes from arachidonic acid. Acute treatment involves epinephrine injected subcutaneously initially and then intravenously. Antihistamines such as diphenhydramine are administered intravenously or intramuscularly.

·         Only fumarate is an intermediate of both the citric acid and urea cycles.

·         High blood levels of amino acids, in addition to glucose, promote the release of insulin through their action on receptors at the surface of the β-cells of the pancreas. Although insulin alone could lead to a hypoglycemic effect, hypoglycemia should not be observed because glucagon is also released in response to the elevated levels of circulating amino acids.

·         Calcium ions and calcium deposits are virtually universal in the structure and function of living things. In humans, calcium ions are required for the activity of many enzymes. Calcium is taken up from the gut in the presence of forms of vitamin D, such as cholecalciferol. Calcium is also primarily excreted through the intestine. When soluble, it is present as a divalent cation. When insoluble, it is found as hydroxyapatite (calcium phosphate) in bone.

·         There are certain properties of metabolism that are considered truisms.

(1) Futile cycles involving useless synthesis and degradation of a fuel do not occur simultaneously.

(2) Acetyl CoA or substances that produce it, such as fatty acids or ketogenic amino acids, cannot be precursors of glucose.

(3) ATP is a major phosphate donor and energy source; it must be present in cells at all times in order for them to function.

(4) Protein phosphorylation inactivates enzymes that store glycogen and fat and activates enzymes that increase blood glucose and fatty acids.

(5) Low blood glucose stimulates gluconeogenesis and glycogenolysis.

(6) Low energy levels stimulate glycolysis and lipolysis.

(7) High energy levels inhibit glycolysis and β-oxidation of fatty acids.

GTP can be a phosphate donor (e.g., in the phosphoenolpyruvate carboxykinase reaction of gluconeogenesis) but ATP is much more common. The acetylation of pyruvate to citric acid by pyruvate dehydrogenase rather than its reduction by lactate dehydrogenase is a key regulatory step between high energy yields of citric acid cycle/oxidative phosphorylation or lower energy yields of glycolysis.

·         A deficiency in carnitine, carnitine acyltransferase I, carnitine acyltransferase II, or acylcarnitine translocase can lead to an inability to oxidize long-chain fatty acids. This occurs because all of these components are needed to translocate activated long-chain (>10 carbons long) fatty acyl CoA across mitochondrial inner membrane into the matrix where β-oxidation takes place. Once long-chain fatty acids are coupled to the sulfur atom of CoA on the outer mitochondrial membrane, they can be transferred to carnitine by the enzyme carnitine acyltransferase I, which is located on the cytosolic side of the inner mitochondrial membrane. Acyl carnitine is transferred across the inner membrane to the matrix surface by translocase. At this point the acyl group is reattached to a CoA sulfhydryl by the carnitine acyltransferase II located on the matrix face of the inner mitochondrial membrane.