outline 27.1 digestion of proteins 27.2amino acid metabolism: an overview 27.3amino acid catabolism:...

Outline

27.1 Digestion of Proteins

27.2 Amino Acid Metabolism: An Overview

27.3 Amino Acid Catabolism: The Amino Group

27.4 The Urea Cycle

27.5 Amino Acid Catabolism: The Carbon Atoms

27.6 Biosynthesis of Nonessential Amino Acids

Goals1. What happens during the digestion of proteins, and what

are the fates of the amino acids? Be able to list the sequence of events in the digestion of proteins, and describe the nature of the amino acid pool.

2. What are the major strategies in the catabolism of amino acids? Be able to identify the major reactions and products of amino acid catabolism and the fate of the products.

3. What is the urea cycle? Be able to list the major reactants and products of the urea cycle.

4. What are the essential and nonessential amino acids, and how, in general, are amino acids synthesized?

Be able to define essential and nonessential amino acids, and describe the general strategy of amino acid biosynthesis.


• The end result of protein digestion is simple—the hydrolysis of all peptide bonds to produce a collection of amino acids.


• Food is converted into smaller, more digestible portions, increasing the surface area of the food to be digested.

• In the acidic environment of the stomach (pH 1–2), the tertiary and secondary structures of proteins begin to unfold.

• Gastric secretions include pepsinogen, a zymogen that is activated by acid to give the enzyme pepsin. Pepsin is stable and active at pH 1–2.

• Pepsin breaks peptide bonds.


• The polypeptides produced by pepsin enter the small intestine, where the pH is about 7–8.

• Pepsin is inactivated, and a group of pancreatic zymogens is secreted. The activated enzymes (proteases such as trypsin, chymotrypsin, and carboxypeptidase) then take over further hydrolysis of peptide bonds in the partially digested proteins.

• The combined action of the pancreatic proteases in the small intestine and other proteases in the cells of the intestinal lining completes the conversion of dietary proteins into free amino acids.

• After active transport across cell membranes lining the intestine, the amino acids are absorbed directly into the bloodstream.


• The amino acid pool occupies a central position in protein and amino acid metabolism.

• All tissues and biomolecules are constantly being degraded, repaired, and replaced.

• Amino acids continuously enter the pool from digestion and breakdown of old protein.

• They are continuously being withdrawn for synthesis of new nitrogen-containing biomolecules.


• Each amino acid is degraded via its own unique pathway, but the general scheme is the same for each one.

General scheme for amino acid catabolism

• Removal of the amino group

• Use of nitrogen in synthesis of new nitrogen compounds

• Passage of nitrogen into the urea cycle

• Incorporation of the carbon atoms into compounds that can enter the citric acid cycle


• Our bodies do not store nitrogen-containing compounds and ammonia is toxic to cells.

• Amino nitrogen must either be incorporated into urea and excreted, or used in the synthesis of new nitrogen-containing compounds:– Nitric oxide (NO, a chemical messenger)– Hormones– Nicotinamide (in coenzymes)– Heme (as part of hemoglobin in red blood cells)– Purine and pyrimidine bases (for nucleic acids)


• Nitrogen oxide (NO) is a particularly interesting molecule: – Chemically, it is a free radical and therefore

very reactive. – Biologically, it lowers blood pressure, kills

invading bacteria, and enhances memory. – Nitric oxide is synthesized from oxygen and

the amino acid arginine. – In blood vessels, NO activates reactions in

smooth muscle cells that cause dilation and a resulting decrease in blood pressure.


• The carbon atoms of amino acids are converted to compounds that can enter the citric acid cycle.

• They continue through the citric acid cycle to give CO2 and energy stored in ATP.

• About 10–20% of our energy is produced in this way.

• If not needed immediately for energy, the carbon-carrying intermediates enter storage as triacylglycerols, glycogen, or ketone bodies.


• In transamination, the amino group of the amino acid and the keto group of an -keto acid change.


• A number of transaminase enzymes are responsible for “transporting” an amino group from one molecule to another.

• Most are specific for -ketoglutarate as the amino group acceptor and work with several amino acids.

• The -ketoglutarate is converted to glutamate, and the amino acid is converted to an -keto acid.


• Transamination is a key reaction in many biochemical pathways.

• The reactions are reversible and go easily in either direction, depending on the concentrations of the reactants.

• Amino acid concentrations are regulated by keeping synthesis and breakdown in balance.

• Oxidative deamination: Conversion of an amino acid —NH2 group to an -keto group, with removal of NH4

+.


• The glutamate from transamination serves as an amino group carrier.

• Glutamate can be used to provide amino groups for the synthesis of new amino acids, but most of the glutamate formed in this way is recycled to regenerate -glutarate.


• The ammonium ion formed in this reaction proceeds to the urea cycle where it is eliminated in the urine as urea.

27.4 The Urea Cycle

• Ammonia is highly toxic to living things and must be eliminated in a way that does no harm.

• Fish are able to excrete ammonia through their gills directly into their watery surroundings.

• Mammals must find other ways to get rid of ammonia, and must first convert ammonia, in solution as ammonium ion, to nontoxic urea via the urea cycle.

27.4 The Urea Cycle

• The conversion of ammonium ion to urea takes place in the liver.

• From there, urea is transported to the kidneys and transferred to urine for excretion.

• Like many other biochemical pathways, urea formation begins with an energy investment. Ammonium ion, bicarbonate ion, and ATP combine to form carbamoyl phosphate in the mitochondrial matrix.

27.4 The Urea Cycle

• Two ATP are invested and one phosphate is transferred to form carbamoyl phosphate, an energy-rich phosphate ester like ATP.

27.4 The Urea Cycle

Steps 1 and 2 of the Urea Cycle: BuildingUp a Reactive Intermediate

• The first step of the urea cycle transfers the carbamoyl group, H2NC=O, from carbamoyl phosphate to ornithine, an amino acid not found in proteins, to give citrulline, another nonprotein amino acid.

• This exergonic reaction introduces the first urea nitrogen into the urea cycle.

27.4 The Urea Cycle

Steps 1 and 2 of the Urea Cycle: BuildingUp a Reactive Intermediate

• In step 2, a molecule of aspartate combines with citrulline in a reaction driven by conversion of ATP to AMP and pyrophosphate followed by the additional exergonic hydrolysis of pyrophosphate.

• Both nitrogen atoms destined for elimination as urea are now bonded to the same carbon atom in argininosuccinate.

27.4 The Urea Cycle

Steps 3 and 4 of the Urea Cycle:Cleavage and Hydrolysis of the Step 2Product

• Step 3 cleaves argininosuccinate into two pieces: arginine, an amino acid, and fumarate, which is an intermediate in the citric acid cycle.

• In Step 4 the hydrolysis of arginine takes place to give urea and regenerate the reactant in Step 1 of the cycle, ornithine.

27.4 The Urea Cycle

27.4 The Urea Cycle

We can summarize the results of the ureacycle as follows:

• Formation of urea from the carbon of CO2, NH4

+, and one nitrogen from the amino acid aspartate, followed by biological elimination through urine

• Breaking of four high-energy phosphate bonds to provide energy

• Production of the citric acid cycle intermediate, fumarate

27.4 The Urea Cycle

27.4 The Urea Cycle

Gout: When Biochemistry Goes Awry• Gout is caused by the precipitation of sodium urate crystals in joints. The pain of gout

results from a cascade of inflammatory responses.• Understanding the many possible causes of the crystal formation is far from

complete.• Uric acid is an end product of the breakdown of purine nucleosides. Loss of its acidic

H gives urate ion.• Anything that increases the production of uric acid or inhibits its excretion in the urine

is a possible cause of gout.• One significant cause of increased uric acid production is accelerated breakdown of

ATP, ADP, or AMP. Alcohol abuse, inherited fructose intolerance, glycogen storage diseases, and circulation of poorly oxygenated blood accelerate uric acid production by this route

• Conditions that diminish excretion of uric acid include kidney disease, dehydration, hypertension, lead poisoning, and competition for excretion from anions produced by ketoacidosis.

• One treatment for gout relies on allopurinol, a structural analog of hypoxanthine, a precursor of xanthine in the formation of urate. Allopurinol inhibits the enzyme for conversion of hypoxanthine and xanthine to urate. Since hypoxanthine and xanthine are more soluble than sodium urate, they are more easily eliminated.

27.4 The Urea Cycle

The Importance of Essential Amino Acids and Effects of Deficiencies • “Essential” nutrients, must be harvested daily from the foods we eat. • There are nine essential amino acids: histidine, isoleucine, leucine, lysine,

methionine, phenylalanine, threonine, tryptophan, and valine. • Histidine: Deficiency can cause pain in bony joints and may have a link to rheumatoid

arthritis.• Isoleucine, Leucine, and Valine: These hydrophobic amino acids are essential for the

production and maintenance of body proteins.• Lysine: Deficiency can lead to poor appetite, reduction in body weight, anemia, and a

reduced ability to concentrate, as well as pneumonia, kidney disease (nephritis), and acidosis, as well as with malnutrition and rickets in children.

• Methionine: Methionine deficiency may ultimately lead to chronic rheumatic fever in children, hardening of the liver (cirrhosis), and nephritis.

• Phenylalanine: Deficiency of phenylalanine can lead to behavioral changes such as psychotic and schizophrenic behavior.

• Threonine: This amino acid is key in the formation of collagen, elastin, and tooth enamel. Its deficiency can result in irritability in children .

• Tryptophan: It has been used to help relieve insomnia, migraines and mild depression. A deficiency of tryptophan can lead to a broad array of emotional and behavioral problems.


• The carbon atoms of each protein amino acid arrive by distinctive pathways at pyruvate, acetyl-CoA, or one of the citric acid cycle intermediates.

• Eventually, all of the amino acid carbon skeletons can be used to generate energy.

• Amino acids that are converted to acetoacetyl-CoA or acetyl-CoA enter the ketogenesis pathway, and are called ketogenic amino acids.

• Those amino acids that proceed by way of oxaloacetate to the gluconeogenesis pathway are known as glucogenic amino acids.


• Humans are able to synthesize about half of the 20 amino acids found in proteins.

• These are known as the nonessential amino acids because they do not have to be supplied by our diet.

• The remaining amino acids, the essential amino acids, are synthesized only by plants and microorganisms. Humans must obtain the essential amino acids from food.


• Meats contain all of the essential amino acids.

• Foods that do not have all of them are described as having incomplete amino acids.

• Dietary deficiencies of the essential amino acids can lead to a number of health problems.

• Food combinations that together contain all of the amino acids are complementary sources of protein.


• We synthesize the nonessential amino acids in pathways containing one to three steps.

• Synthesis of essential amino acids by other organisms is complicated, requiring many steps and a substantial energy investment.

• Nonessential amino acid One of 11 amino acids that are synthesized in the body and are therefore not necessary in the diet.

• Essential amino acid An amino acid that cannot be synthesized by the body and thus must be obtained in the diet.


• All of the nonessential amino acids derive their amino groups from glutamate, the molecule that picks up ammonia in amino acid catabolism and carries it into the urea cycle.

• Glutamate can also be made from NH4+ and

-ketoglutarate by reductive deamination, the reverse of oxidative deamination.

• The same glutamate dehydrogenate enzyme carries out the reaction.


• Glutamate also provides nitrogen for the synthesis of other nitrogen-containing compounds, including the purines and pyrimidines that are part of DNA.

• The following four common metabolic intermediates are the precursors for synthesis of the nonessential amino acids:


• Glutamine is made from glutamate, and asparagine is made by reaction of glutamine with aspartate.


• The amino acid tyrosine is classified as nonessential because we can synthesize it from phenylalanine, an essential amino acid.


• In 1947 it was found that failure to convert phenylalanine to tyrosine causes phenylketonuria (PKU).

• PKU results in elevated blood serum and urine concentrations of phenylalanine, phenylpyruvate, and metabolites produced when the body diverts phenylalanine to metabolism by other pathways.

• Undetected, PKU causes mental retardation by the second month of life. Widespread screening of newborn infants is the only defense against PKU and similar treatable metabolic disorders that take their toll early in life.

Chapter Summary

1. What happens during the digestion of proteins, and what is the fate of the amino acids?

• Protein digestion begins in the stomach and continues in the small intestine. The result is virtually complete hydrolysis to yield free amino acids.

• The amino acids enter the bloodstream after active transport into cells lining the intestine.

• The body does not store nitrogen compounds, but amino acids are constantly entering the amino acid pool from dietary protein or broken down body protein and being withdrawn from the pool for biosynthesis or further catabolism.

Chapter Summary, Continued

2. What are the major strategies in the catabolism of amino acids?

• Each amino acid is catabolized by a distinctive pathway, but in most of them the amino group is removed by transamination (the transfer of an amino group from an amino acid to a keto acid), usually to form glutamate.

• Then, the amino group of glutamate is removed as ammonium ion by oxidative deamination. The ammonium ion is destined for the urea cycle.

• The carbon atoms from amino acids are incorporated into compounds that can enter the citric acid cycle. These carbon compounds are also available for conversion to fatty acids or glycogen for storage, or for synthesis of ketone bodies.

Chapter Summary, Continued

3. What is the urea cycle? • Ammonium ion (from amino acid catabolism) and

bicarbonate ion (from carbon dioxide) react to produce carbamoyl phosphate, which enters the urea cycle.

• The first two steps of the urea cycle produce a reactive intermediate in which both of the nitrogens that will be part of the urea end product are bonded to the same carbon atom. Then arginine is formed and split by hydrolysis to yield urea, which will be excreted.

• The net result of the urea cycle is reaction of ammonium ion with aspartate to give urea and fumarate.

Chapter Summary, Continued4. What are the essential and nonessential amino

acids, and how, in general, are amino acids synthesized?

• Essential amino acids must be obtained in the diet because our bodies do not synthesize them.

• They are made only by plants and microorganisms, and their synthetic pathways are complex.

• Our bodies do synthesize the so-called nonessential amino acids. Their synthetic pathways are quite simple and generally begin with pyruvate, oxaloacetate, -ketoglutarate or 3-phosphoglycerate. The nitrogen is commonly supplied by glutamate.

outline 27.1 digestion of proteins 27.2amino acid metabolism: an overview 27.3amino acid catabolism:...

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