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PROTEIN TURNOVER AND NITROGEN ECONOMY
- proteins metabolism has a balance between body’s energy and synthetic needs
- dietary protein required to synthesize endogenous proteins (albumin, myosin, actin)
- essential amino acids cannot be synthesize by body; others can be synthesized from carbon
sources
-table
- protein balance  relationship between synthesis and degradation (proteolysis) of proteins;
2. roles of proteolysis: activation of enzymes (zymogens), blood clotting cascade, control of
organ growth, digestion of dietary protein, fuel supply (starvation), maintain amino acid pools,
regulate enzyme activity (removing enzyme from cell, half-lives), remove abnormal proteins,
tissue repair
- starvation  glucose produced from amino acids (muscle proteins serves as fuel supply)
- to provide for proper balance during growth, proteolysis counterbalances synthesis to control
organ size
- if dietary intake of amino acids > requirement for protein synthesis  new body protein
synthesis (positive balance) or body protein levels maintained at stable level (neutral balance)
- positive nitrogen balance  occurs during growth when intake and storage of nitrogen
exceed excretion of nitrogen; also associated with restoration of atrophied muscles or body
building
- if protein intake is insufficient or if balance of amino acids ingested is incorrect for synthetic
needs  endogenous protein catabolized to liberate free amino acids for synthesis of essential
proteins (negative nitrogen balance); associated with starvation and trauma; occurs when rate
of proteolysis exceeds rate of protein synthesis (decrease rate of synthesis or accelerated
digestion)
- elemental constituents of amino acids: carbon  CO2; hydrogen  H2O; nitrogen  urea or
ammonia; sulfur  to SO421.
- insulin and glucocorticoids participate in regulation of protein turnover and nitrogen economy
- insulin  increase synthesis, decrease degradation of endogenous proteins; favors
maintenance of body protein pools; insulin-like growth factor (ILGF) promotes protein
synthesis during growth
- glucocorticoids (released during stress or starvation)  peripheral tissue catabolism
- ala is a precursor for glucose synthesis; glucocorticoid catabolic effect coincides with ability of
this class of hormones to promote gluconeogenesis
- insulin:glucocorticoid ratio determines net protein turnover; fed state  high ratio 
protein formation; fasting  insulin falls, low ratio  protein mobilized via proteolysis; trauma
 glucocorticoids increase, low ratio  protein mobilized via proteolysis
- endogenous protein degradation occurs in lysosome and cytoplasm; membrane/extracellular
proteins cycle through lysosome (proteolysis); lysosome is acidic; proteolysis in cytoplasm
(calpains, Ca2+ dependent)
3. AMMONIA METABOLISM AND REMOVAL OF NITROGEN WASTE
Transamination reactions
- 1st step in amino acid degradation is removal of amino nitrogen group by transferring it to
alpha-ketoglutarate (alpha-KG) to produce glu; catalyzed by
aminotransferase/transaminases (cofactor is pyridoxal phosphate)
- pyridoxal phosphate derived from vitamin B6 (also cofactor in glycogen phosphorylase and
lysyl oxidase); deficiency  dermatitis, anemia, convulsions
- transaminases are reversible; alpha-ketoacid accepts amino group from glu to produce new
amino acid; most common aminotransferases are for alanine (pyruvate) and aspartate
(oxaloacetate); aminotransferases test for liver damage
- transaminases transfer nitrogen to glutamate in non-hepatic tissues (muscle) to rid excess
nitrogen from those tissues
- in liver, nitrogen dumped onto glutamate as an initial step in conversion of nitrogen to
excreted form  urea
Overview of nitrogen excretion
- body removes nitrogenous waste; some of these produces are from special starting materials
while urea provides a means of removing nitrogen waste in a general manner
- kidney can excrete NH4+ as part of acidification mechanism of urine
- look at table
Nitrogen removal from nonhepatic tissues
- glutamate dehydrogenase; one direction  reaction involves addition of nitrogen to alphaketoglutarate as ammonia (non-hepatic tissues, remove harmful ammonia from these tissues)
- glutamate non transported across plasma membrane, but glutamine easily leaves cells
- glutamine formed through addition of a second ammonia molecule by glutamine synthetase
to produce glutamine; glutamine processed by kidney, which contains glutaminase  (with
glutamate dehydrogenase) removes amino groups from glutamine resulting in alpha-KG and
ammonia; ammonia released in this manner excreted in urine
4. UREA CYCLE
- liver  glutamate produced by transamination gives up its nitrogen as free ammonia via
glutamate dehydrogenase for eventual synthesis of urea (excreted)
1. Carbamoyl phosphate synthetase-I
- urea cycle in liver (kidney)
- provides means of ridding body of nitrogen waste as urea
- ammonia from amino acids by combined actions of transamination and glutamate
dehydrogenase
- mitochondria  ammonia incorporated into carbamoyl phosphate via carbamoyl
phosphate synthetase-I (CPS-1)  reaction product, carbamoyl phosphate, provides
substrate for cycle; reaction requires one ATP molecule providing phosphate that combines
with CO2 and ammonia and the other ATP molecule provides driving force for reaction (2
ATP)
- carbamoyl phosphate directly introduces the first source of nitrogen for the cycle
- CPS-1 is allosterically activated by N-acetylglutamate (produced by enzyme-catalyzed
reaction of acetyl CoA + glutamate  N-acetylglutamate + CoA)
- mitochondrial CPS-1 (CPS1: NH3 nitrogen source) distinguished from cytoplasmic CPS-2
(CPS-2: glutamine nitrogen source) in that CPS-2 is involved with pyrimidine synthesis
2. Ornithine transcarbamoylase
- first reaction of urea cycle: carbamoyl phosphate combines with ornithine  citrulline via
ornithine transcarbamoylase (occurs in mitochondrial matrix)
- ornithine transported into mitochondria form cytoplasm
- citrulline product released from mitochondria to cytoplasm in exchange for ornithine
3. Arginosuccinate synthetase
- cytoplasm  citrulline reacts with aspartate via arginosuccinate synthetase yielding
arginosuccinate
- aspartate formed by transamination of glutamate with oxaloacetate
- aspartate is 2nd direct source of nitrogen for the cycle
- energy requiring reaction that cleaves ATP  AMP + PPi (costs two high-energy P bonds, PPi
splits spontaneously into two Pi)
4. Arginosuccinase
- arginosuccinate cleaved by arginosuccinase into fumarate and arginine
- fumarate reconverted to oxaloacetate in citric acid cycle  can regenerate aspartate;
carbons from aspartate recycled with only nitrogen claimed for urea cycle
5. Arginase
- arginine cleaved to urea and ornithine (into cytoplasm in exchange for citrulline)
- urea secreted by liver into blood to be cleared by kidney
- when arginase cannot handle accumulation of arginine  arginine stimulates formation of Nacetylglutamate to increase formation of carbamoyl phosphate  reacts with ornithine to
produce a mass action effect on arginase reaction thus increasing formation of urea
5. HYPERAMMONEMIA
Acquired hyperammonemia
- results from collateral circulation of portal system in response to liver damage (cirrhosis);
blood flow from intestines bypasses liver
- collateral circulation (non cirrhosis) responsible for hyperammonemia; microorganisms in GI
tract produce large amount of ammonia absorbed in portal system and sent to liver for detox;
portal-systemic shunting  blood flows directly to IVC (bypasses liver)  portal-systemic
encephalopathy (PSE)
- shunting results in reduction of ammonia detoxification by liver; ammonia from amino
acid/protein metabolism cannot be converted to urea to an extent causing blood ammonia to
rise
- liver transplant; reduce absorption of ammonia using lactulose  fermented by
microorganisms to short chain organic acids that lower pH of intestinal lumen: converts NH3 to
NH4+ (not readily absorbed across intestinal epithelium and is excreted in stool)
Inherited hyperammonemia
- caused by deficiencies of urea cycle enzymes
- severity depends on proximity of defect to point of entry of ammonia in its processing to urea
- CPS-1 defects or ornithine transcarbamoylase defects  severe hyperammonemia; these
two defects can be distinguished by evaluating appearance of pyrimidines in urine; defect in
ornithine transcarbamoylase  CPS-1 accumulates in mitochondria  excess carbamoyl
phosphate leaks in to cytoplasm  increases rate of pyrimidine synthesis
- X-linked, in males
- high ammonia leads to mental retardation; possible reasons for neurologic damage:
1. ammonia reacts with alpha-ketoglutarate to form glutamate thus interfering with ATP
production in citric acid cycle
2. excess glutamate formed undergoes amination to glutamine and then to alphaketoglutaramic acid, a neurotoxic compound
3. high ammonia  increase blood levels of some amino acids; these compete with other amino
acids for transport across blood-brain barrier; thus, predominant transport of one or a few
amino acids limits availability of other amino acids within the brain  reduction in normal rate
of protein synthesis
Treatment
- restrict dietary protein  reduce amount of ammonia that must be detoxified
- alternative ammonia excretion mechanisms use body’s detox of exogenous chemicals
- benzoic acid  conjugated with glycine to form hippuric acid  readily excreted in
urine taking with it the nitrogen from glycine; glycine is synthesized from CO2 and NH3
- phenylacetic acid  conjugated with glutamine forming phenylacetylglutamine 
excreted in urine taking two nitrogens per molecule; glutamine continually synthesized in
hyperammonemia in peripheral tissues (muscle) via glutamate dehydrogenase and
glutamine synthetase reactions