Introduction to Metabolism Flashcards
Intermediary metabolism
Intermediary metabolism is the name given to the sequences of biochemical reactions that degrade, synthesize, or interconvert small molecules inside living cells.
Metabolic Pathways
Metabolism occurs in small discrete steps, each of which is catalyzed by an enzyme.
**The term metabolic pathway refers to a particular set of reactions that carries out a certain function or functions. **
The pathway of gluconeogenesis or glucose synthesis, for example, operates mainly during a period of fasting, and its primary function is to maintain the concentration of glucose in the circulation at levels that are required by glucose-dependent tissues such as the brain and red blood cells.
Another example of a metabolic pathway is the tricarboxylic acid (TCA) cycle, which oxidizes the two carbons of acetyl-coenzyme A (acetyl-CoA) to CO2 and water, thus completing the catabolism of carbohydrates, fats (fatty acids), and proteins (amino acids).
Metabolic Intermediates
Biochemical pathways are comprised of organic compounds called metabolic intermediates, all of which contain carbon, hydrogen, and oxygen.
Some metabolic intermediates also contain nitrogen or sulfur.
In most instances, these compounds
themselves have no function.
An exception would be a compound such as citric acid, which is both an intermediate in the TCA cycle and a key regulator of other pathways,
including oxidation of glucose (glycolysis) and gluconeogenesis.
Homeostasis
Homeostasis refers to an organism’s tendency or drive to maintain the normalcy of its internal environment, including maintaining the concentration of nutrients and metabolites within relatively strict limits.
A good example is glucose homeostasis.
In the face of widely varying physiological conditions, such as fasting or exercise, both of which tend to lower blood glucose, or following the consumption of a carbohydrate meal that raises the blood glucose concentration, the human body activates hormonal mechanisms that operate to maintain blood glucose within rather narrow limits, 80 to 100 mg/dL (Fig. 1-1).
Hypoglycemia (low blood glucose) stimulates the release of gluconeogenic hormones such as glucagon and hydrocortisone, which promote
the breakdown of liver glycogen and the synthesis of glucose in the liver (gluconeo-
genesis), followed by the release of glucose into the blood. On the other hand, hyperglycemia (elevated blood glucose) stimulates the release of insulin, which promotes the uptake of glucose and its utilization, storage as glycogen, and conversion to fat.
Maintenance of the blood calcium concentration between strict limits is another example of homeostasis. The normal total plasma calcium concentration is in the
range 8.0 to 9.5 mg/dL. If the calcium concentration remains above the upper limit of normal for an extended period of time, calcium may deposit, with pathological consequences in soft tissues such as the heart and pancreas.
Hypocalcemia (a.k.a. tetany)
can result in muscle paralysis, convulsions, and even death; chronic hypocalcemia causes rickets in children and osteomalacia in adults. The body uses vitamin D and certain hormones (e.g., parathyroid hormone, calcitonin) to maintain calcium homeostasis.
WHAT DO METABOLIC PATHWAYS ACCOMPLISH?
- Generation of Energy
- Degradation or Catabolism of Organic Molecules
- Synthesis of Cellular Building Blocks and Precursors of Macromolecules
- Storage of Energy
- Excretion of Potentially Harmful Substances
- Generation of Regulatory Substances
WHAT DO METABOLIC PATHWAYS ACCOMPLISH?
Generation of Energy
**The primary dietary fuels for human beings are carbohydrates and fats (triacylglycerols). The human body also obtains energy from dietary protein and for some people-ethanol. **
Metabolism of these fuels generates energy, much of which is captured as the high-energy molecule adenosine triphosphate (ATP).
The ATP can be used for biosynthetic processes (e.g., protein synthesis), muscle contraction, and active transport of ions and other solutes across membranes.
WHAT DO METABOLIC PATHWAYS ACCOMPLISH?
Degradation or Catabolism of Organic Molecules
Catabolic pathways usually involve cleavage of C-0, C-N, or C-C bonds.
Most intracellular catabolic pathways are oxidative and involve transfer of reducing equivalents hydrogen atoms to nicotinamide-adenine dinucleotide (NADf) or flavine-adenine dinucleotide (FAD).
The reducing equivalents in the resulting NADH or FADH2 can then be used in biosynthetic reactions or transferred to the mitochondria electron-transport chain for generation of ATP.
Degradation or Catabolism of Organic Molecules
1) Digestion. Before dietary fuels can be absorbed into the body, they must
be broken down into simpler molecules. Thus, starch is hydrolyzed to yield glucose,
and proteins are hydrolyzed to their constituent amino acids.
2) Glycolysis. Glycolysis is the oxidation of glucose into the three-carbon
compound pyruvic acid.
3) Fatty Acid Oxidation. The major route of fatty acid degradation is
beta-oxidation, which accomplishes stepwise two-carbon cleavage of fatty acids into acetyl-Co A.
4) Amino Acid Catabolism. Breakdown of most of the 20 common amino acids is initiated by removal of the alpha-amino group of the amino acid via transamination. The resulting carbon skeletons are then further catabolized to generate energy or are used to synthesize other molecules (e.g., glucose, ketones). The nitrogen atoms of amino acids can be utilized for the synthesis of other nitrogenous compounds, such
as heme, purines, and pyrimidines. Excess nitrogen is excreted in the form of urea.
WHAT DO METABOLIC PATHWAYS ACCOMPLISH?
Synthesis of Cellular Building Blocks and Precursors of Macromolecules
Gluconeogenesis: Synthesis of Glucose. This pathway produces glucose from glycerol, pyruvate, lactate, and the carbon skeletons of certain (glucogenic) amino acids. Gluconeogenesis is crucial to maintaining an adequate supply of glucose to the brain during fasting and starvation.
Synthesis of Fatty Acids. Excess dietary carbohydrates and the carbon
skeletons of ketogenic amino acids are catabolized to acetyl-CoA, which is then
utilized for the synthesis of long-chain (C16 and C18) fatty acids. Storage of these
fatty acids as adipocyte triacylglycerols provides the major fuel source during the
fasted state.
Synthesis of Heme. Heme is a component of the oxygen-binding proteins hemoglobin and myoglobin. Heme also functions as part of cytochromes, both in the mitochondria1 electron transport chain involved in respiration-dependent ATP synthesis and in certain oxidation-reduction enzymes, such as the microsomal mixed-function oxygenases (e.g., cytochrome P450). Although most heme synthesis occurs in hemopoietic tissues (e.g., bone marrow), nearly all cells of the body synthesize heme for their own cytochromes and heme-containing enzymes.
WHAT DO METABOLIC PATHWAYS ACCOMPLISH?
Storage of Energy
Cells have only a modest ability to accumulate ATP, the major high-energy molecule in human metabolism. The human body can store energy in various forms, described below.
**1. Creatine Phosphate. **Most cells, especially muscle, can store a limited
amount of energy in the form of creatine phosphate. This is accomplished by a
reversible process catalyzed by creatine kinase:
ATP + creatine + creatine phosphate + ADP
When a cell’s need for energy is at a minimum, the reaction tends toward the right.
By contrast, when the cell requires ATP for mechanical work, ion pumping, or as
substrate in one biosynthetic pathway or another, the reaction tends to the left, thereby making ATP available.
2. Glycogen. Glycogen is the polymeric, storage form of glucose. Nearly all of the body’s glycogen is contained in muscle (approximately 600 g) and liver (approximately 300 g), with small amounts in brain and type I1 alveolar cells in the lung. Glycogen serves two very different functions in muscle and liver. Liver glycogen is utilized to maintain a constant supply of glucose in the blood. By contrast, muscle glycogen does not serve as a reservoir for blood glucose. Instead, muscle glycogen is broken down when that tissue requires energy, releasing glucose, which is subsequently oxidized to provide energy for muscle work.
3. Fat or Triacylglycerol. Whereas the body’s capacity to store energy in the form of glycogen is limited, its capacity for fat storage is almost limitless. After a meal, excess dietary carbohydrates are metabolized to fatty acids in the liver.
Whereas some of these endogenously synthesized fatty acids, as well as some of the fatty acids obtained through the digestion of dietary fat, are used directly as fuel by peripheral tissues, most of these fatty acids are stored in adipocytes in the form of triacylglycerols. When additional metabolic fuel is required during periods of fasting or exercise, the triacylglycerol stores in adipose are mobilized and the fatty acids are made available to tissues such as muscle and liver
WHAT DO METABOLIC PATHWAYS ACCOMPLISH?
Excretion of Potentially Harmful Substances
1. Urea Cycle. This metabolic pathway takes place in the liver and synthesizes urea from the ammonia (ammonium ions) derived from the catabolism of amino acids and pyrimidines. Urea synthesis is one of the body’s major mechanisms for detoxifying and excreting ammonia.
2. Bile Acid Synthesis. Metabolism of cholesterol to bile acids in the liver serves two purposes: (1) it provides the intestine with bile salts, whose emulsifying properties facilitate fat digestion and absorption, and (2) it is a mechanism for disposing of excess cholesterol. Humans cannot break open any of the four rings of
cholesterol, nor can they oxidize cholesterol to carbon dioxide and water. Thus, biliary excretion of cholesterol-both as cholesterol per se and as bile salts-is the only mechanism the body has for disposing of significant quantities of cholesterol.
3. Heme Catabolism. When heme-containing proteins (e.g., hemoglobin,
myoglobin) and enzymes (e.g., catalase) are turned over, the heme moiety is oxi-
dized to bilirubin, which after conjugation with glucuronic acid is excreted via the
hepatobiliary system.
WHAT DO METABOLIC PATHWAYS ACCOMPLISH?
Generation of Regulatory Substances
Metabolic pathways generate molecules that play key regulatory roles.
As indicated above, citric acid (produced in the TCA cycle) plays a major role in coordinating the activities of the pathways of glycolysis and gluconeogenesis.
Another example of a regulatory molecule is 2,3-bisphosphoglyceric acid, which is produced in a side reaction off the glycolytic pathway and modulates the affinity of hemoglobin for oxygen.
GENERAL PRINCIPLES COMMON TO METABOLIC PATHWAYS
- ATP Provides Energy for Synthesis
- Many Metabolic Reactions Involve Oxidation or Reduction
- Only Certain Metabolic Reactions Occur in Human Metabolism
- Some Organic Molecules Are Nutritionally Essential to Human Health
- Some Metabolic Pathways Are Irreversible or Contain Irreversible Steps
- Metabolic Pathways Are Interconnected
- Metabolic Pathways Are Not Necessarily Linear
- Metabolic Pathways Are Localized to Specific Compartments Within the Cell
- A Different Repertoire of Pathways Occurs in Different Organs
- Different Metabolic Processes Occur in the Fed State Than During Fasting
- Metabolic Pathways Are Regulated
GENERAL PRINCIPLES COMMON TO METABOLIC PATHWAYS
ATP Provides Energy for Synthesis
Anabolic or synthetic pathways require input of energy in the form of the high-energy bonds of ATP, which is generated directly during some catabolic reactions (such as glycolysis) as well as during mitochondria1 oxidative phosphorylation.
GENERAL PRINCIPLES COMMON TO METABOLIC PATHWAYS
Many Metabolic Reactions Involve Oxidation or Reduction
During catalysis, oxidative reactions transfer reducing equivalents (hydrogen atoms) to cofactors such as NAD+, NADP+ (nicotinamide-adenine dinucleotide phosphate) or FAD.
Reduced NADH and FADH2 can then be used to generate ,4TP through oxidative phosphorylation in mitochondria.
NADPH is the main source of reducing equivalents for anabolic, energy-requiring pathways such as fatty acid and cholesterol synthesis.
