lec 4 (mcbride) - protein turnover and AA catabolism

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50 Terms

1

maintaining homeostasis…

requires metabolic regulation that coordinates the use of nutrient pools

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2

protein digestion and turnover

  • AA are obtained from diet when proteins are digested

  • cellular proteins are degraded to AA b/c of damage, misfolding, or changing metabolic demands

  • excess AA CANNOT be stored or excreted → must be used as metabolic fuel

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protein production and consumption rates…

are controlled to maintain physiological levels and function

  • homeostatic mechanisms adjust these rates to achieve production = consumption to maintain a physiological concentration required for life

<p>are controlled to maintain physiological levels and function</p><ul><li><p>homeostatic mechanisms adjust these rates to achieve production = consumption to maintain a physiological concentration required for life</p></li></ul><p></p>
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proteins are degraded to…

amino acids

  • dietary proteins are degraded to AA which are absorbed by the intestine and transported in the blood

  • essential AA = AA that CANNOT be synthesized and must be acquired in the diet

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essential AA

in humans CANNOT be synthesized from other dietary precursors

  • histidine

  • isoleucine

  • leucine

  • lysine

  • methionine

  • phenylalanine

  • threonine

  • tyrptophan

  • valine

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digestion of dietary proteins

begins in the stomach and is completed in the intestine

  • protein digestion begins in the stomach where the acidic environment denatures proteins into random coils

  • pepsin = the primary proteolytic enyzme of the stomach

    • max active at pH 2

  • partly digested proteins move from the stomach → beginning of the small intestine (duodenum) → stimulating secretion of sodium bicarbonate and proteolytic enzymes from the pancreas

  • aminopeptidases in the plasma membrane of intestinal cells enhance digestion

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products of protein digestion…

are absorbed by the small intestine

  • free AA, dipeptides, and tripeptides are transported into the intestinal cells

  • at least 7 different transporters exist, each specific to a different group of AA

  • absorbed AA are released into the blood by a number of Na+-AA antiporters

<p>are absorbed by the <strong>small intestine</strong></p><ul><li><p>free AA, dipeptides, and tripeptides are transported into the <strong>intestinal cells</strong></p></li><li><p>at <u>least 7</u> different transporters exist, each specific to a different group of AA</p></li><li><p>absorbed AA are released into the blood by a number of <strong>Na+-AA antiporters</strong></p></li></ul><p></p>
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cellular proteins are degraded at…

different rates

  • protein turnover = the degradation and resynthesis of proteins

    • takes place constantly in cells

    • essential for removing short-lived or damaged proteins

  • the half-lives of proteins range over several orders of magnitude

    • ornithine decarboxylase, which catalyzes the synthesis of poly amines, is ~11 mins

    • hemoglobin = life of RBC

    • lens protein crystallin = life of organism

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protein turnover

is tightly regulated

  • ubiquitin = a small (76 aa) that tags proteins for destruction

    • present in all eukaryotic cells

    • highly conserved

  • ubiquitin attaches by the carboxyl-terminal Gly residue to the ε-amino groups of +1 lys residues on target protein

    • requires ATP hydrolysis

    • forms an isopeptide bond because ε rather than α-amino groups are targeted 

<p>is tightly regulated</p><ul><li><p>ubiquitin = a small (76 aa) that tags proteins for <strong>destruction</strong></p><ul><li><p>present in <u>all eukaryotic cells</u></p></li><li><p><strong>highly </strong>conserved</p></li></ul></li><li><p>ubiquitin attaches by the <u>carboxyl-terminal Gly residue </u>to the <span><u>ε-amino groups of +1 lys residues</u> on target protein</span></p><ul><li><p>requires <strong>ATP hydrolysis</strong></p></li><li><p>forms an isopeptide bond because <u>ε </u><span><u>rather than α-amino groups </u>are targeted&nbsp;</span></p></li></ul></li></ul><p></p>
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ubiquitin

is a small, compact protein with 7 lysine residues

  • has an extended carboxyl terminus which is activated and linked to proteins targeted for destruction

<p>is a small, compact protein with <strong>7 lysine residues</strong></p><ul><li><p>has an <strong>extended carboxyl terminus</strong> which is <strong>activated</strong> and <strong>linked</strong> to proteins targeted for destruction</p></li></ul><p></p>
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3 enzymes participate in the attachment of ubiquitin to protein

  • ubiquitin-activating enzyme (E1) = adenylates ubiquitin and transfers it to a sulfhydryl group of a Cys residue of E1

  • ubiquitin-conjugating enzyme (E2) = transfer ubiquitin to one of its own sulfhydryl groups

  • ubiquitin-protein ligase (E3) = transfers ubiquitin from E2 to an ε-amino group of target protein

    • brings E2 and target protein together

    • ubiquitin be transffered directly or be passed to a cys residue of E3 first

<ul><li><p>ubiquitin-activating enzyme (E1) = <strong>adenylates</strong> ubiquitin and transfers it to a sulfhydryl group of a <strong>Cys </strong>residue of E1</p></li><li><p>ubiquitin-conjugating enzyme (E2) = transfer ubiquitin to one of its own sulfhydryl groups</p></li><li><p>ubiquitin-protein ligase (E3) = transfers ubiquitin from E2 to an ε-amino group of target protein</p><ul><li><p>brings E2 and target protein together</p></li><li><p>ubiquitin be transffered directly or be passed to a cys residue of E3 first</p></li></ul></li></ul><p></p>
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multiple ubiquitin molecules are typically…

added to a single protein substrate

  • E3 can remain bound to target protein and generate a chain of ubiquitin molecules

  • E3 can dissociate after the first ubiquitin addition and a chain can be extended by another E2/E3 pair

  • ubiquitin can be added onto any of the 7 Lys or the N-terminus of the previous ubiquitin

  • a chain of 4+ ubiquitin molecules linked via Lys 48 = especially effective signal for protein degradation

<p>added to a single protein substrate</p><ul><li><p>E3 can remain bound to target protein and generate a chain of ubiquitin molecules</p></li><li><p>E3 can dissociate after the <strong>first</strong> ubiquitin addition and a chain can be extended by another E2/E3 pair</p></li><li><p>ubiquitin can be added onto any of the <u>7 Lys</u> or the <u>N-terminus</u> of the previous ubiquitin</p></li><li><p>a chain of 4+ ubiquitin molecules linked via <strong>Lys 48</strong> = especially effective signal for protein degradation</p></li></ul><p></p>
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E3 ubiquitin ligases provide…

the protein target specificity

  • in humans:

    • 2 E1 ligase genes

    • 30-50 E2 ligase genes

    • over 600 E3 ligase genes

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in a tetraubiquitin chain…

4 ubiquitin molecules are linked by isopeptide bonds

  • the ε-amino group of a Lys residue of 1 ubiquitin is linked to the terminal carboxylate of another

  • this unit = primary signal for degradation when linked to target protein

<p>4 ubiquitin molecules are linked by <strong>isopeptide bonds</strong></p><ul><li><p>the <u>ε-amino group of a Lys residue</u> of 1 ubiquitin is linked to the <u>terminal carboxylate</u> of another</p></li><li><p>this unit = <strong>primary signal</strong> for degradation when linked to target protein</p></li></ul><p></p>
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degrons

are amino acid sequences that control protein half lifew

  • degron = specific sequence of AA that indicate a protein should be degraded

  • for many proteins, the amino-terminal residue AA (N-degron) = important degradation signal for E3 enzyme

    • may only be exposed after proteolytic cleavage

    • may be added after protein synthesis

    • may require other modifications

  • other degrons include cyclin destruction boxes and PEST sequences

<p>are amino acid sequences that control <strong>protein half lifew</strong></p><ul><li><p>degron = specific sequence of AA that indicate a protein should be <strong>degraded</strong></p></li><li><p>for many proteins, the amino-terminal residue AA (N-degron) = important degradation signal for <strong>E3 enzyme</strong></p><ul><li><p>may only be exposed <strong>after</strong> proteolytic cleavage</p></li><li><p>may be added <strong>after</strong> protein synthesis</p></li><li><p>may require other modifications</p></li></ul></li><li><p>other degrons include cyclin destruction boxes and PEST sequences</p></li></ul><p></p>
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cytoplasmic yeast

dependence of the half-lives of cytoplasmic yeast proteins on the identity of their amino-terminal residues

  • highly stabilizing residues (half life > 20 hours)

    • ala

    • cys

    • gly

    • met

    • pro

    • ser

    • thr

    • val

  • intrinsically destabilizing residues (half life = 2-30 mins)

    • arg

    • his

    • lie

    • leu

    • lys

    • phe

    • trp

    • tyr

  • destabilizing resides after chemical modification (half life = 3-30 mins)

    • asn

    • asp

    • gln

    • glu

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importance of E3 proteins to normal cell function

  • proteins that are NOT degraded b/c of a defective E3 may accumulate → causing a disease of protein aggregation

  • angelman syndrome = severe neurological disorder characterized by an unusually happy disposition, cognitive disability, absence of speech, uncoordinated movement, and hyperactivity

    • caused a defect in a member of E3 family

  • overexpression of E3 ligase causes autism

  • inappropriate protein turnover → cancer

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additional roles of ubiquitination

  • ubiquitination also regulates proteins involved in:

    • DNA repair

    • chromatin remodeling

    • innate immunity

    • membrane trafficking

    • autophagy

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the proteasome

digests the ubiquitin-tagged proteins

  • proteasome (26S proteasome) = a large, ATP-driven protease complex that digests ubiquitinated proteins

  • the 26S proteasome = complex of 2 components

    • one 20S catalytic unit arranged as barrel

    • two 19S regulatory units that control access to the interior of the 20S catalytic subunit

<p>digests the ubiquitin-tagged proteins</p><ul><li><p>proteasome (26S proteasome) = a large, ATP-driven protease complex that digests ubiquitinated proteins</p></li><li><p>the 26S proteasome = complex of 2 components </p><ul><li><p><strong>one</strong> <strong>20S</strong> catalytic unit arranged as barrel</p></li><li><p><strong>two 19S</strong> regulatory units that control access to the interior of the 20S catalytic subunit</p></li></ul></li></ul><p></p>
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functions of the 19S regulatory unit

  • the 19S regulatory units:

    • contain ubiquitin receptors that bind specifically to polyubiquitin chains

    • uses ATP to unfold polyubiquitinated chains and direct them into catalytic core

    • contains an isopeptidase that cleaves off intact ubiquitin molecules so they can be reused

  • key components of the 19S complex = 7 ATPases of the AAA+ class

    • a class of chaperone-like ATPases associated with:

      • assembly

      • operation

      • and disassembly of protein complexes

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20S proteasome

is barrel-shaped and made up of 28 homologous subunits

  • the subunits (α-type, red; β-type, blue) are arranged in 4 rings of 7 subunits each

  • some of the β-type subunits (right) include protease active sites at their amino termini

<p>is barrel-shaped and made up of <strong>28</strong> homologous subunits</p><ul><li><p>the subunits<span>&nbsp;(α-type, red; β-type, blue) are arranged in <strong>4 rings of 7 subunits</strong> each </span></p></li><li><p><span>some of the β-type subunits (right) include protease active sites at their amino termini</span></p></li></ul><p></p>
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proteolytic active sites of the 20S barrel

  • there are 3 types of active sites in the β subunit, each with different specificity

    • chymotrypsin-like: cleaves after large hydrophobic amino acids

    • trypsin-like: cleaves after basic amino acids

    • caspase-like: cleaves after acidic amino acids

  • all active sites employ an N-terminal Thr residue

    • the OH group of the Thr residue attacks the carbonyl groups of peptide bonds → forms acyl-enzyme intermediates

    • substrates are degraded in a processive manner WITHOUT intermediate release

    • substrates are reduced to peptides ranging from 7-9 residues before release

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the proteasome and other proteases generate

free amino acids

  • ubiquitinated proteins are processed to peptide fragments

  • ubiquitin is removed and recycled prior to protein degradation

  • peptide fragments are further digested to yield free AA which can be used for biosynthetic reactions; most notably protein synthesis

    • alternatively, the amino group can be removed and processes to urea and the carbon skeleton can be used to synthesize carbohydrate or fats or used directly as fuel for cellular respiration

<p>free amino acids</p><ul><li><p>ubiquitinated proteins are processed to <strong>peptide fragments</strong></p></li><li><p>ubiquitin is <strong>removed and recycled</strong> prior to protein degradation</p></li><li><p>peptide fragments are further digested to yield free AA which can be used for biosynthetic reactions; most notably protein synthesis</p><ul><li><p>alternatively, the amino group can be <strong>removed</strong> and processes to <strong>urea</strong> and the carbon skeleton can be used to synthesize <strong>carbohydrate or fats</strong> or used directly as <strong>fuel</strong> for cellular respiration</p></li></ul></li></ul><p></p>
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processes regulated by protein degradation

  • many biological processes are controlled, at least in part, by protein degradation via the ubiquitin-proteasome pathway

  • processes regulated by protein degradation

    • gene transcription

    • cell-cycle progression

    • organ formation

    • inflammatory response

    • tumor suppression

    • cholesterol metabolism

    • antigen processing

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protein degradation can be used to regulate…

biological function

  • bortezomib (velcade) = dipeptidyl boronic acid inhibitor of the proteasome

    • used as therapy for multiple myeloma

  • degrons = used as regulatory mechanisms for protein expression

  • HT1171 = suicide inhibitor of the proteasome of M. tuberculosis

    • has NO effect on human proteasomes

<p>biological function</p><ul><li><p>bortezomib (velcade) = dipeptidyl boronic acid <strong>inhibitor</strong> of the proteasome</p><ul><li><p>used as therapy for multiple myeloma</p></li></ul></li><li><p>degrons = used as regulatory mechanisms for protein expression</p></li><li><p>HT1171 = suicide <strong>inhibitor</strong> of the proteasome of M. tuberculosis</p><ul><li><p>has NO effect on human proteasomes</p></li></ul></li></ul><p></p>
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first step in amino acid degradation

is the removal of nitrogen

  • AA NOT needed as building blocks are degraded to compounds able to enter the metabolic mainstream

  • amino group is removed and remaining carbon skeleton is metabolized to glycolytic intermediate or to acetyl CoA

  • major site of AA degradation in mammals = liver

  • muscles also readily degrade the branched-chain AAs (leu, Ile and Val)

<p>is the removal of <strong>nitrogen</strong></p><ul><li><p>AA NOT needed as building blocks are degraded to compounds able to enter the metabolic mainstream</p></li><li><p>amino group is <strong>removed</strong> and remaining carbon skeleton is metabolized to g<u>lycolytic intermediate</u> or to <u>acetyl CoA</u></p></li><li><p>major site of AA degradation in mammals = <strong>liver</strong></p></li><li><p>muscles also readily degrade the <strong>branched-chain AAs</strong> (leu, Ile and Val)</p></li></ul><p></p>
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alpha-amino groups

are converted into ammonium ions by oxidative deamination of glutamate in liver

  • α-amino groups → α-ketoglutarate → yielding glutamate

  • glutamate is oxidatively deaminated in the liver to yield ammonium ion (NH4+)

<p>are converted into <strong>ammonium ions</strong> by <u>oxidative deamination of glutamate</u> in liver</p><ul><li><p><span>α-amino groups → α-ketoglutarate → yielding glutamate</span></p></li><li><p><span>glutamate is <strong>oxidatively deaminated</strong> in the liver to yield ammonium ion (NH4+)</span></p></li></ul><p></p>
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role of aminotransferases

  • aminotransferases (transminases) = catalyze the transfer of α-amino group from an α-amino acid → α-ketoacid

    • reaction are reversible and can be used to synthesize amino acids from α-ketoacids

<ul><li><p>aminotransferases (transminases) = catalyze the transfer of<span> α-amino group from an α-amino acid → α-ketoacid</span></p><ul><li><p>reaction are <strong>reversible</strong> and can be used to synthesize amino acids from <span>α-ketoacids</span></p></li></ul></li></ul><p></p>
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aspartate aminotransferase and alanine aminotransferase

  • aspartate aminotransferase = catalyze the transfer of amino group of aspartate → α-ketoglutarate; end result = oxaloacetate + glutamate

  • alanine aminotransferase = catalyze the transfer of the amino group of alanine → α-ketoglutarate; end result = pyruvate + glutamate

<ul><li><p>aspartate aminotransferase = <strong>catalyze</strong> the transfer of amino group of aspartate → <span>α-ketoglutarate; end result = oxaloacetate + glutamate</span></p></li><li><p><span>alanine aminotransferase = <strong>catalyze</strong> the transfer of the amino group of alanine → α-ketoglutarate; end result = pyruvate + glutamate</span></p></li></ul><p></p>
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blood levels of aminotransferase serve as…

diagnostic function for liver damage

  • the presence of alanine and aspartate aminotransferase in the blood = indication of liver damage

  • liver damage can occur due to:

    • viral hepatitis

    • long-term excessive alcohol consumption

    • reaction to drugs

  • in cases of liver damage, liver cell membranes are damaged and aminotransferases leak into blood

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aminotransferases require…

pyridoxal phosphate (PLP) from vitamin B6

  • aminotransferases require the coenzyme pyridoxal phosphate (PLP) - a derivative of pyridoxine (vitamin B6)

<p>pyridoxal phosphate (PLP) from vitamin B<sub>6</sub> </p><ul><li><p>aminotransferases require the coenzyme pyridoxal phosphate (PLP) - a derivative of pyridoxine (vitamin B6)</p></li></ul><p></p>
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transamination

  • step 1

    • transfer of amino acid group from amino acid substrate → PLP and release of keto acid

    • example: for alanine aminotransferase, AA = alanine and released ketoacid is pyruvate

  • step 2

    • transfer of amino acid from coenzyme → keto acid → new amino acid

    • example: for alanine aminotransferase, the ketoacid is α-ketoglutarate and the released AA is glutamate

<ul><li><p>step 1</p><ul><li><p>transfer of amino acid group from amino acid substrate → PLP and release of keto acid</p></li><li><p>example: for alanine aminotransferase, AA = alanine and released ketoacid is pyruvate</p></li></ul></li><li><p>step 2</p><ul><li><p>transfer of amino acid from coenzyme → keto acid → new amino acid</p></li><li><p>example: for alanine aminotransferase, the ketoacid is <span>α-ketoglutarate and the released AA is glutamate</span></p></li></ul></li></ul><p></p>
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pyridoxal phosphate enzymes

catalyze a wide array of reactions

  • at the α-carbon of amino acids, PLP-dependent enzymes catalyze:

    • decarboxylations

    • deaminations

    • racemizations

    • aldol clevages

  • at the β-carbon and γ-carbon of AA, PLP-dependent enzymes catalyze elimination and replacement rxn

<p>catalyze a wide array of reactions</p><ul><li><p>at the <span><strong>α-carbon </strong>of amino acids, PLP-dependent enzymes catalyze:</span></p><ul><li><p>decarboxylations</p></li><li><p>deaminations</p></li><li><p>racemizations</p></li><li><p>aldol clevages</p></li></ul></li><li><p>at the <span>β-carbon and γ-carbon of AA, PLP-dependent enzymes catalyze <strong>elimination and replacement</strong> rxn</span></p></li></ul><p></p>
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role of glutamate dehydrogenase

  • glutamate dehydrogenase = a mitochondrial enzyme that converts the nitrogen atom in glutamate → free ammonia ion by oxidative deamination

    • is essentially a liver-specific enzyme

    • can use either NAD+ or NADP+

    • proceeds by dehydrogenation of the C-N bond, followed by hydrolysis of the ketimine

    • allosterically inhibited by GTP and stimulated by ADP in mammals

<ul><li><p>glutamate dehydrogenase = a <u>mitochondrial</u> enzyme that converts the <strong>nitrogen</strong> atom in glutamate → <strong>free ammonia ion</strong> by <strong>oxidative deamination</strong></p><ul><li><p>is essentially a liver-specific enzyme</p></li><li><p>can use either NAD+ or NADP+</p></li><li><p>proceeds by <u>dehydrogenation</u> of the <strong>C-N</strong> bond, followed by <strong>hydrolysis</strong> of the ketimine</p></li><li><p>allosterically <strong>inhibited</strong> by GTP and <strong>stimulated</strong> by ADP in mammals</p></li></ul></li></ul><p></p>
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serine and threonine can be…

directly deaminated

  • serine dehydratase and threonine dehydratase directly deaminate their respective AA

    • PLP = prosthetic group (non-protein component that is tightly bound to protein and essential for biological function)

  • NO transfer of the α-amino group to α-ketoglutarate is required

  • dehydration precedes deamination

    • serine → pyruvate + NH4+

    • threonine → α-ketobutyrate + NH4+

<p>directly deaminated</p><ul><li><p>serine dehydratase and threonine dehydratase <strong>directly deaminate </strong>their respective AA</p><ul><li><p>PLP = prosthetic group (non-protein component that is tightly bound to protein and essential for biological function)</p></li></ul></li><li><p>NO transfer of the <span>α-amino group to α-ketoglutarate is required</span></p></li><li><p><span>dehydration <strong>precedes</strong> deamination</span></p><ul><li><p>serine → pyruvate + NH4+ </p></li><li><p>threonine → α-ketobutyrate + NH4+</p></li></ul></li></ul><p></p>
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fate of the ammonia ion

  • in most terrestrial vertebrates, NH4+ converted into urea → excreted

  • sum of the reactions of aminotransferases and glutamate dehydrogenase is → second equation in image

<ul><li><p>in most terrestrial vertebrates, NH4+ converted into urea → <strong>excreted</strong></p></li><li><p>sum of the reactions of aminotransferases and glutamate dehydrogenase is → second equation in image</p></li></ul><p></p>
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peripheral tissues transport…

nitrogen to the liver

  • muscles use branched-chain AA as fuel during prolonged exercise and fasting

  • muscles lack enzymes of the urea cycle

  • nitrogen is transported from muscleliver as alanine (through glutamate) in the glucose-alanine cycle

  • glutamine synthetase = catalyzes the synthesis of glutamine from glutamate and NH4+

    • nitrogens of glutamine can be eliminated by incorporation into urea in the liver

<p>nitrogen to the liver</p><ul><li><p>muscles use <strong>branched-chain AA</strong> as fuel during prolonged exercise and fasting</p></li><li><p>muscles <strong>lack</strong> enzymes of the urea cycle</p></li><li><p><u>nitrogen</u> is transported from <strong>muscle</strong> → <strong>liver </strong>as <strong>alanine</strong> (through glutamate) in the glucose-alanine cycle</p></li><li><p>glutamine synthetase = catalyzes the synthesis of glutamine from glutamate and NH4+ </p><ul><li><p>nitrogens of glutamine can be <strong>eliminated</strong> by incorporation into urea in the liver </p></li></ul></li></ul><p></p>
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pathway integration: the glucose-alanine cycle

allows muscle cells to use AA as fuel

  • during prolonger exercise and fasting, muscles use branched-chain AA as fuel

  • nitrogen removed is transferred (through glutamate) to alanine which is released into the blood stream

  • in the liver, alanine is taken up and converted into pyruvate for the subsequent synthesis of glucose

<p>allows muscle cells to use AA as fuel</p><ul><li><p>during prolonger exercise and fasting, muscles use <strong>branched-chain AA</strong> as fuel</p></li><li><p><u>nitrogen</u> <strong>removed</strong> is transferred (through glutamate) to <u>alanine</u> which is released into the blood stream</p></li><li><p>in the liver, <u>alanine</u> is taken up and <strong>converted</strong> into <u>pyruvate</u> for the subsequent synthesis of glucose</p></li></ul><p></p>
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urea cycle

eliminates both nitrogen and carbon waste products

  • 2 nitrogen atoms enter the cycle and leave as urea

  • carbon dioxide is simultaneously eliminated as it is hydrated to bicarbonate which then enters the cycle

<p><strong>eliminates</strong> both nitrogen and carbon waste products</p><ul><li><p><strong>2 nitrogen atoms</strong> enter the cycle and <strong>leave</strong> as urea</p></li><li><p>carbon dioxide is simultaneously <strong>eliminated</strong> as it is hydrated to bicarbonate which then <strong>enters</strong> the cycle</p><p></p></li></ul><p></p>
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urea cycle begins with…

formation of carbamoyl phosphate

  • carbamoyl phosphate synthetase I = catalyzes the coupling of ammonia (NH3) with bicarbonate (HCO3-) → form carbamoyl phosphate

    • occurs in mitochondria

    • mammals have 2 isozymes

    • requires 2 molecules of ATP, making reaction essentially irreversible

<p>formation of <strong>carbamoyl phosphate</strong></p><ul><li><p>carbamoyl phosphate synthetase I = <strong>catalyzes</strong> the coupling of ammonia (NH3) with bicarbonate (HCO3-) → form carbamoyl phosphate</p><ul><li><p>occurs in <strong>mitochondria</strong></p></li><li><p>mammals have <strong>2 isozymes</strong></p></li><li><p>requires <strong>2 molecules of ATP</strong>, making reaction essentially <strong>irreversible</strong></p></li></ul></li></ul><p></p>
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carbamoyl phosphate synthetase I is…

the key regulatory enzyme for urea synthesis

  • carbamoyl phosphate synthetase I:

    • requires the allosteric regulator N-acetylglutamate for activity

    • is inhibited by acetylation and stimulated by deactylation

  • N-acetylglutamate synthase = catalyzes the synthesis of N-acectylglutamate

    • activated when AA are readily available

<p>the key regulatory enzyme for <strong>urea synthesis</strong></p><ul><li><p>carbamoyl phosphate synthetase I:</p><ul><li><p>requires the <u>allosteric regulator N-acetylglutamate</u> for activity </p></li><li><p>is <strong>inhibited</strong> by acetylation and <strong>stimulated</strong> by deactylation</p></li></ul></li><li><p>N-acetylglutamate synthase = catalyzes the <strong>synthesis</strong> of <u>N-acectylglutamate</u></p><ul><li><p><strong>activated</strong> when AA are readily available </p></li></ul></li></ul><p></p>
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carbamoyl phosphate reacts with…

ornithine to begin urea cycle

  • ornithine transcarbamoylase = catalyzes the transfer of the carbamoyl group of carbamoyl phosphate to ornithine forming citrulline

    • occurs in the mitochondria

  • citrulline is transported into the cytoplasm

<p>ornithine to begin urea cycle</p><ul><li><p>ornithine transcarbamoylase = <strong>catalyzes </strong>the transfer of the <strong>carbamoyl group</strong> of carbamoyl phosphate to <strong>ornithine</strong> forming <strong>citrulline</strong></p><ul><li><p>occurs in the mitochondria</p></li></ul></li><li><p>citrulline is transported into the <strong>cytoplasm</strong></p></li></ul><p></p>
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citrulline

condenses with aspartate

  • aspartate is the donor of the second nitrogen of urea

  • argininosuccinate synthetase = catalyzes the condensation of citrulline and aspartate → argininosuccinate

    • occurs in cytoplasm

    • requires ATP

<p>condenses with aspartate</p><ul><li><p>aspartate is the donor of the <strong>second nitrogen of urea</strong></p></li><li><p>argininosuccinate synthetase = catalyzes the <strong>condensation</strong> of citrulline and aspartate → argininosuccinate</p><ul><li><p>occurs in <strong>cytoplasm</strong></p></li><li><p>requires <strong>ATP</strong> </p></li></ul></li></ul><p></p>
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cleavage of argininosuccinate

  • argininosuccinase = cleaves argininosuccinate → arginine and fumarate

<ul><li><p>argininosuccinase = <strong>cleaves</strong> argininosuccinate → arginine and fumarate</p></li></ul><p></p>
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45

hydrolysis of arginine

  • arginase = hydrolyzes arginine to generate urea and ornithine

  • ornithine is transported back into mitochondria

  • urea is excreted

<ul><li><p>arginase = <strong>hydrolyzes</strong> arginine to generate <strong>urea and ornithine</strong></p></li><li><p>ornithine is <strong>transported back</strong> into mitochondria</p></li><li><p>urea is <strong>excreted</strong></p></li></ul><p></p>
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46

urea cycle is linked to gluconeogenesis

  • the stoichiometry of the urea cycle = photo

  • fumarate is hydrated to malate which is in turn oxidized oxaloacetate

  • oxaloacetate can be:

    • converted into glucose by gluconeogenesis

    • transaminated to aspartate for another round of urea synthesis

<ul><li><p>the stoichiometry of the urea cycle = photo</p></li><li><p><u>fumarate</u> is <strong>hydrated</strong> to malate which is in turn <strong>oxidized</strong> <u>oxaloacetate</u></p></li><li><p>oxaloacetate can be:</p><ul><li><p>converted into <strong>glucose</strong> by gluconeogenesis</p></li><li><p><strong>transaminated</strong> to <u>aspartate</u> for another round of urea synthesis</p></li></ul></li></ul><p></p>
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47

nitrogen metabolism is…

integrated with other metabolic pathways

  • urea cycle, gluconeogenesis, and the transamination of oxaloacetate are linked by fumarate and aspartate

<p>integrated with other metabolic pathways</p><ul><li><p>urea cycle, gluconeogenesis, and the transamination of oxaloacetate are linked by <strong>fumarate and aspartate</strong></p></li></ul><p></p>
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48

inherited defects of the urea cycle…

cause hyperammonemia and can lead to brain damage

  • any defect in the urea cycle leads to an elevated level of NH4+ in the blood (hyperammonemia)

  • high levels of NH4+ may:

    • inappropriately activate an Na+-K+-Cl- cotransporter, disrupting the osmotic balance of the nerve cell and causing cellular swelling

    • disrupt neurotransmitter systems

    • impact energy metabolism, levels of oxidative stress, nitric oxide synthesis and signal transduction pathways

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49

argininosuccinase deficiency

can be managed by supplementing the diet with arginine

  • argininosuccinate deficiency is treated by:

    • restricting total protein intake

    • supplementing the diet with arginine

  • excess nitrogen is excreted in the form of argininosuccinate

<p>can be managed by supplementing the diet with arginine</p><ul><li><p>argininosuccinate deficiency is treated by:</p><ul><li><p><strong>restricting</strong> total protein intake</p></li><li><p>supplementing the diet with arginine</p></li></ul></li><li><p><strong>excess nitrogen</strong> is excreted in the form of argininosuccinate</p></li></ul><p></p>
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50

both carbamoyl phosphate synthetase and ornithine transcarbamylase deficiencies…

can be treated with supplementation

  • by supplementing the diet with benzoate and phenylacetate, excess nitrogen can be excreted in the form of hippurate and phenylacetylglutamine

<p>can be treated with supplementation</p><ul><li><p>by supplementing the diet with benzoate and phenylacetate, <strong>excess nitrogen</strong> can be <strong>excreted</strong> in the form of <u>hippurate and phenylacetylglutamine </u></p></li></ul><p></p>
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