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61 terms

Amino Acid Metabolism

Major Purposes of Amino Acid Metabolism
1)They are substrates for the generation of metabolic energy
2)Substrates for **PROTEIN** synthesis
-->Human body proteins are degraded AND resynthesized continously
3)Substrates for the synthesis of many products (Ex. Heme, purines, pyrimidines, several coenzymes, melanin, & the biogenic amines
Essential Amino Acids ("MTT. VIP HALL" -> "Mister VIP HALL
-->The 9 AA (10 if you count arginine, which is considered semi-essential depending on the individual's age) that must be supplied in the diet:
1)M: Methionine
2)T: Theorinine
3)T: Tryptophan
4)V: Valine
5)I: Isoleucine
6)P: Phenylanaline
7)H: Histidine
8)A: Arginine
9)L: Lysine
10)L: Leucine
-->***AA are not stored by the body (unlike fats & CHO)
-->Therefore, AA must be either:
1)Obtained from the diet
2)Synthesized de novo
3)Produced from normal protein degradation
-->Any AA in EXCESS of the biosynthetic needs of the cell are rapidly degraded
Features of the Amino Acid Pool
-->Represent the AA's released by the hydrolysis of dietary or tissue protein mix with other free AA's distributed throught the body
-->Is **100g in a 70 kg man**
-->Major inputs into the AA pool that are interchangeable:
1)Tissue protein, plasma protein, enzymes, hormones, antibodies, hemoglobin
2)Other new AA;s
3)Non-protein compouds (non-protein compounds, heme, hterocyclic amines
-->Major Output of AA's:
1)**CO, H20, & Urea**
2)Glucose, Glycogen, Lipids
Classification of Amino Acids
1)Ketogenic Amino Acids (**Leucine & Lysine**)
2)Gluconeogenic & Ketogenic Amino Acids
(***Larger Amino Acids, including Isoleucine, Phenylalanine, Tyrptophan, & Tyrosine)
3)Ketogenic AA
--->All other AA's
Gluconeogenic AA
-->Amino acids whos catabolism yields pyruvate or one of the intermediates of the citric acid cycle
-->Substrates for gluconeogenesis (which can give rise to the net formation of glucose in the LIVER & KIDNEY)
Ketogenic AA
-->AA whose catabolism yields either acetoacetate or one of the precursors
2 AA that contribute to the transport of AA to the liver (esp. during FASTING)
Protein Turnover (Rate of synthesis = Rate of Degredation)
-->Keeps the total amount of protein at a constant level
-->Leads to the hydrolysis & resynthesis of **300-400g** of body protein each day
-->Varies widely for individual proteins
-->Major Functions:
1) Prevents accumulation of abnormal proteins & harmful peptides
2)Controls & regulates the rate of a metabolic reaction by controlling the rate of syn & catabolism of enzymes
Types of Proteins involved during protein turnover
1)Short Lived Protein (Ex. Regulatory proteins & misfolded proteins)
-->Rapidly degraded (1/2 life measured in minutes or hours)
2)Long Lived Protein (1/2 life of days to weeks)
-->Constitute the majority of proteins in the cell
3)Structural Proteins (Ex. Collegen; 1/2 life measured in months or years)
General Features of Ubiquitin-Proteasome Pathway (UPP)
-->Ubiquitin directs protein recycling
-->Majority of **intracellular proteins** are degraded by the UPP pathway
-->**Extracellular proteins** & some surface proteins are taken up via ENDOCYTOSIS & are degraded within the LYSOSOMES
PEST Sequence that attaches to ubiquitin (labelling them for destruction)
2)E --> Glutamate
Nitrogen Balance
-->The difference btwn the nitrogen entering the body & that leaving it
-->A normal adult with adequate protein intake should be in **nitrogen equilibrium**
Positive Nitrogen Balance (+ NB)
-->Is observed when nitrogen intake exceeds nitrogen excretion
-->Examples of patients with + NB:
1)Pregnant Women
2)Young Growing Children
3)Adults Recovering from a major illnes
4)Body Builders
Negative Nitrogen Balance (- NB)
-->When nitrogen intake is less than nitrogen excretion
-->Examples of patients with a -NB:
1)Wasting Diseases, Chronic infections, Cancer or any other serious disease
Insufficient quantities of ONE AA
-->Is enough to turn a normal individual with a postitive NB to a negative NB
Amount of proteins that are converted to AA by digestive enzymes
-->***70-100 grams
3 areas that are responsible for protein degredation
1)The Stomach
2)The Pancreas
3)The Small intestine
**The is NO digestion in the mouth**
-->Is the region where protein digestion begins
-->Secretion of **gastric juice** occurs, with the production of 2 molecules:
1)Hydrochloric Acid (HCl)
2)Pepsinongen (Proenzyme)
-->Produced by **Parietal Cells of Stomach** as PEPSINOGEN
-->Major fxn is to DENATURE dietary protein to make it more susceptible to proteolysis
-->A coagulation enzyme that is important **only in infants**, and is absent from the stomach of adults
-->Causes the coagulation of milk ("curdles milik), thus prevents the rapid passage of milk from the stomach
-->Produced in infants for milk protein digestion because infants can't digest any other protein except milk
1)his hormone changes to pepsin at 1 year old
-->A protease with a low pH optimum (pH=2.0)
-->Catalyzes the cleavage of pesinogen to pepsin (***auto-activation) when exposed to HCl
-->Is considered an **enopeptidase**, but can cleave peptide bonds at the ends of the polypeptide
Digestion of protein in the intestine
-->The partially digested material from the stomach is mixed with pancreatic secretion that inclues HCO3- & a group of proteolytic enzymes
-->HCO3- neutralizes the stomach acid, & making the pH BASIC for the digestive enzymes to act
Highlightes of Dietary Protein by proteases from the pancrease
-Pancreatic **Endopeptidase** which cleave peptide bonds within protein chain digest polypeptide to smaller fragments.
-Trypsin cleaves peptide bonds in which COOH group is contributed by **argininine or lysine**
-Trypsin is secreted as inactive zymogen, trypsinogen.
-Trypsinogen is cleaved to form trypsin by the enzyme enteropeptidase (enterokinase).
-Trypsinogen may also undergo auto activation by trypsin.
Features of Chymotrypsin
-->secreted as Chymotrypsinogen
-->usually cleaves peptide bonds in which the carboxyl group COOH contributed by the *aromatic amino acids* or by *leucine**
-->Is coverted to trypsin by trypsin
Features of Elastase
-->Elastase cleaves at the carboxyl end of amino acid residues with small uncharged side chains such as:
-->Cleaves the zymogen proelastase to elastase
Exopeptidases from the pancreas (cleaved from zymogen to active form by trypsin)
-->Major examples are ***Carboxypeptidase A (aromatic) & Carboxypeptidase B (basic)
-->Are cleaved to the active enzymatic form by trypsin
-->Act on amino acids at **C*terminal end of the peptide (vs. *aminopeptidases**)
Enzymes of Protein Digestion
Trypsin --> Arginine & Lsyine
Chomotyrpsin --> Aromatic AA or Leucine
Elastase --> alanine, glycine , or serine
-->Exopeptidases prod. by the intestinal cells that cleave one AA at the **N-terminal**
DI- & Tripeptidases
-->Produce AA's from dipeptides or peptides
Absorbtion of Aminno Acids
-->Are absorbed from the intestinal lumen through **active Na+-dependent transport system & facilitated diffusion**
1)The luminal plasma membrane of the absorptive cell bears at least four sodium-dependent amino acid transporters - one each for acidic, basic, neutral and Imino amino acids.
2)These transporters bind amino acids only after binding sodium.
3)The fully loaded transporter then undergoes a conformational change that dumps sodium and the amino acid into the cytoplasm (& are eventually taken to the portal vein, followed by its reorientation back to the original form.
1)Branched chain amino acids ARE NOT metabolized by the liver --> Sent from the liver primarily to muscle via the blood
Inherited Disorders of AA Transport
1)Hartup Disease
Hartup Disorder
-->Autosomal recessive disorder
-->Characterized by a **defective neutral AA transporter on renal & intestinal epithelial cells**
-->Primarily affects **Tryptophan** (or non-polar AA)
1)Tryptophan is EXCRETED into the urine
2)Decrease absorbtion from the gut
-->Clincal sign is **PELLAGRA**(Diarrhea, Dematitis, & Dementia)
3)Seen in patients that derive most of their diet from corn ("maize")
-->Disease involving defective trans-epithelial transport of **cystine** in the kidney & intestine
-->Characterized by formation of cystine stones ("Staghorn Caniculi") in the **kidneys, urethra, & bladder**
Fate of the Amino Group of the AA's
-->The α-amino groups of amino acids (derived from the diet or the breakdown of tissue proteins (is ultimately secreted into the urine as UREA)
-->The removal of the α-amino groups are divided into 4 processes:
3)Ammonia Transport
4)Reactions of Urea Cycle
-->The transfer of α-amino group (-NH3+) to an α-KG
-->The products are **α-keto acid (from org. AA) & glutamate***
-->Catayzed by a family of enzymes called "Aminotransferases" (Transanimases)
-->The acceptor of the amino group is always **α-KG***
-->Requires **pyridoxal phosphate (PLP)**, a cofactor form of vitamin B6 (a cofactor for all transaminases)
-->All amino acids undergo transaminase reactions EXCEPT ***Lysine, Threonin (undergo deamination reactions)
-->Are **reverisble reactions**, which are important in the synthesis & catabolism of AA
Location of Transaminases
-->Located in the **mitochondria & cytosol** of most tissues (esp. the LIVER)
1)Permits the synthesis of non-essential AA's (using amino groups from other AA's and Carbon skeletons synthesized in a cell)
2 most important aminotranferase rxn's (***see notes)
1)ALT --> Alanine Aminotransferase
2)AST -->Aspartate Aminotransferase
-->Since they are normally **intracellular enzymes**, the presence of elevated plasma levels of aminotransferases indicate DAMAGE TO CELLS RICH IN THESE ENZYMES
-->ALT & AST are elevated in nearly ALL FORMS OF LIVER DISEASE
Ammonia-Forming Reaction involving L-Glutamate Dehydrogenase (***a mitochondrial enzyme***
-->**Oxidation Deamination* by Glutamate Dhydrogenase results in the liberation of the amino group as *free ammonia**(NH3+)
1)Involves the conversion of glutamate to α-KG
-->Occur primarily in the LIVER & KIDNEY
1)Provide α-ketoacids (Ex. Pyruvate) for the central pathway of energy
2)To provide **ammonia* for urea synthesis
-->Catalyses a NET LOSS of nitrogen from the L-glutamate molecule
Allosteric Regulators of Glutamate Dehydrogenase
-->GTP/ATP: *An allosteric inhibitor of glutamate dehydrogenase**
-->Adenosine Diphosphate (ADP/GDP) is an **activator of glutamate dehydrogenase**
-->When the energy levels in the cell are LOW:
1)Glutamate Dehydrogenase activity is HIGH, facilitating ENERGY PRODUCTION from the carbon skeletons derived from AA
-->When the energy levels in the cell are HIGH:
2)Glutamate Dehydrogenase activity is LOW, conserving the breakdown of carbon skeletons derived from AA
Conenzymes involved with L-Glutamate Dehydrogenase
***Is the only enzyme which uses BOTH conenzyme NAD+ & NADH+
2 Major Mechanisms for the transport of ammonia from the peripheral tissues to the liver (for the its ultimate conversion into urea
1)Use of **Glutamine Synthase** in Peripheral Tissue
-->Catalyzes the combination of NH3+ with Glutamate to form **Glutamine* (A **non-toxic transport form of ammonia)
-->Catalyzed by ATP
-->Glutamine moves from the peripheral tissues through the blood to reach the liver
-->IN LIVER: Glutamine is cleaved by **Glutaminase** to reproduce Glutamate & Free NH3
2)Transanimation of Pyruvate in the muscle
-->Transanimation Rxn produces **ALANINE**
-->Alanine is transported into the blood to reach the liver, where it is **transanimated** to form pyruvate (which can be used in gluconeogenesis)
-->The glucose produced via gluconeogenesis can enter the blood to be used by muscle, which is known as the **glucose-alanine cycle**
General Features of the Urea Cycle
-->About 80 percent of the excreted nitrogen is in the form of urea
-->Urea is largely made in the liver.
-->A series of reactions that are distributed between the mitochondrial matrix and the cytosol.
-->The series of reactions that form Urea is known as the Urea cycle or the Krebs - Henseleit Cycle.
-->Blood Urea Level: 20 - 40 mg / dl
-->Urine Urea Level: 20 - 40 gm / daily.
-->Urea is the main non protein nitrogenous compound (NPN).
-->Urea formation is increased in the case of increased protein intake
Feature of Steps of The Urea Cycle
The first two reactions leading to the synthesis of urea occur in the **mitochondria**
-->the remaining cycle enzymes are located in the **Cytosol**
Reactions that involve both the mitochondrial matrix & the cytosol:
1)***Heme Synthesis
3)Urea Cycle
Step 1: The Formation of Carbomoyl Phosphate
-Carbamoyl phosphate is synthesized from NH4+, CO2 and two ATP
-Enzyme: Carbamoyl phosphate synthetase I (CPS I )
-Location :Mitochondria
-Activator: N-acetylglutamate (NAG)
-->The NH3+ (clglutaminase) eaved by is provided by the oxidative deanimation of glutamate by **mitochochodiral glutamate dehydrogenase**
Step 2: Formation of Citrulline
Ornithine reacts with Carbamoyl phosphate to form citrulline.
Enzyme: Ornithine transcarbamoylase
Location: Mitochondria
-->Releases a high energy Phosphate in Reactions
Step 3: Synthesis of Arginosuccinate
Citrulline combines with aspartate to form arginosuccinate
Enzyme: Arginosuccinate synthetase
1 ATP used.
Location: Cytosol
Step 4: Cleavage of Argionosuccinate
Arginosuccinate is cleaved to form arginine and fumarate.
Enzyme: arginosuccinase.
Location: Cytosol.
Stpe 5: Cleavage of Arigine To Ornithine & Urea
Arginine is cleaved to ornithine and urea
Enzyme: Arginase
**Only the liver can cleave Arginine and synthesize urea**
Krebs Bicycle
-->States that the FUMARATE released in the urea cycle is converted to aspartate to ENTER the urea cycle by **cytoplasmic reactions**
Regulation of Urea Cycle via action of Carbamoyl 1-Phosphate (CPS-I)
-->Catalyzes the formation of carbamoyl phosphate from NH3+ & HCO3-
-->As an allosteric enzyme, it is **activated by NAG*(formed from Acetyl CoA), which itself is activated by arginine**
Levels of NAG (N-acetylglutamate)
2)Acetyl CoA
Carbamoyl Phosphate Sythase I vs II(CPS-I vs CPS-II)
-->Is a **mitochondrial enzyme** that forms carbamoyl phosphate destined for inclusion into the urea cycle
-->Is a **cytosolic enzyme** that is involved in pyrimidine nucleotide synthesis
If there is a deficiency in arginase
-->Will only be mild symptoms in the patient b/c you have other nitrogens in the body AND it can be excreted into the urine
Consequences of a Deficiency in CSP-I
1)Buildup of NH4+ in the blood
2)Increased levels of glutamine in the blood
-->Occurs when the hepatic urea cycle cannot handle the increased rates of ammonia generation
-->***IS A MEDICAL EMERGENCY, b/c ammonia has a direct neurotoxic effect on the CNS (Ex. temors, slurring of speech, vomittng, cerebral edema)
-->At high concentrations, ammonia can cause com & death
-->2 Major Types:
1)Acquired Hyperammonemia
2)Heriditary Hyperammonemia
Acquired Hyperammonemia
-->Commonly caused by **liver failure** caused by:
1)Viral Hepetitis
-->Cirrhosis of the liver may result in collateral circulation being formed around the liver, which would lead to less ammonia being converted to urea
Heriditary Hyperammonemia
-->Is due to genetic deficiencies of each of the 5 enzymes
-->Orinithine Transcarbamoylase Deficiency (most common) AFFECTS **MALES*(i.e. is X Linked; all other ones are *autosomal recessive**) predominantly
-->Major Types:
-***Hyperammonemia Type 1 (Carbamoyl phosphate synthase I (CPSI deficiency)
-***Hyperammonemia Type 2 (Ornithine transcarbamoylase)
-Citrullinemia (Argininosuccinate synthase)
Argininosuccinicaciduria (Argininosuccinate lyase)
Hyperargininemia (Arginase)

-->Failure of
Treament of Urea Cycle Disorders
-->The key to treating patients is to ***diagnose EARLY & then aggresively treat compounds that can aid in the nitrogen removal from the patient
-->Specific Treatments:
1)Low-Protein Diets (are essential to reduce the potential for excessive amino acid degredation)
2)Administring compounds that **Covelently bind to AA's (which produce nitrogen-containing mol.) that are excreted into the urine) (Ex. *Phenyacetate**)
-->Condenses with glutamine to form **phenylacetylglutamine** --> which can be EXCRETED
Hyperammonemia Type 1 (Carbamoyl phosphate synthase I (CPSI deficiency) & Orotic Acid
-->Can cause an increase in orotic acid (part of nucleic acid pathway)