synthesis of amino acids
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The catabolism of the amino acids found in proteins involves the removal of -aminogroups, followed by the breakdown of the resulting carbon skeletons. Thesepathways converge to form seven intermediate products:
- oxaloacetate, - -ketoglutarate - pyruvate, -fumarate, - succinyl coenzyme A (CoA), - acetyl CoA, -acetoacetate. These products directly enter the pathways of intermediary metabolism, resulting
either in the synthesis of glucose or lipid or in the production of energy through theiroxidation to CO2 and water by the citric acid cycle.
Nonessential amino acids can be synthesized in sufficient amounts from theintermediates of metabolism or, as in the case of cysteine and tyrosine, fromessential amino acids.
. Genetic defects in the pathways of amino acid metabolism can cause seriousdisease.
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Ketogenic amino acids
Amino acids whose catabolism yields eitheracetoacetate or one of its precursors(acetyl CoA oracetoacetyl CoA) are termed ketogenic
Acetoacetate is one of the ketone bodies, which also
include 3-hydroxybutyrate and acetone. Leucine and lysineare the only exclusively ketogenic
amino acids found in proteins. Their carbon skeletonsare not substrates for gluconeogenesis and, therefore,cannot give rise to the net formation of glucose orglycogen in the liver, or glycogen in the muscle.
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Classification of amino acids
Glucogenic aa:ALA, ASP,ARG,ASN,CIS,GLI,PRO,SER,GLU,GLN,HIS,TRE,MET,VAL
Glucogenic and ketogenic aa:Tyr,Ile, Phe,Trp
Ketogenic:Leu, Lys
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Catabolism of the CarbonSkeletons of Amino Acids
A. Amino acids that form oxaloacetate Asparagineis hydrolyzed by asparaginase,
liberating ammonia and Asp. Asparaginase,which hydrolyzes asparagine to aspartate, canbe administered systemically to treat leukemicpatients. Asparaginase lowers the level ofasparagine in the plasma and, therefore,deprives cancer cells of a required nutrient.
Asp loses its amino group by transamination toform oxaloacetate
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Amino acids that form -ketoglutarate
Glutamineis converted to glutamate and ammonia by the enzymeglutaminase .Glutamate is converted to -ketoglutarate bytransamination, or through oxidative deamination by glutamatedehydrogenase
Proline: This amino acid is oxidized to glutamate. Glutamate istransaminated or oxidatively deaminated to form -ketoglutarate.
Arginine: This amino acid is cleaved by arginase to produceornithine. This reaction occurs primarily in the liver as part of theurea cycle .Ornithine is subsequently converted to -ketoglutarate.
Histidine: This amino acid is oxidatively deaminated by histidase tourocanic acid, which subsequently forms N-formiminoglutamateFIGlu donates its formimino group to tetrahydrofolate, leaving
glutamate.
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Amino acids that form pyruvate
Alanine: This amino acid loses its amino group by transamination toform pyruvate
Serine: This amino acid can be converted to glycine and N5,N10-methylenetetrahydrofolate .Serine can also be converted to pyruvate
by serine dehydratase Glycine: This amino acid can either be converted to serine byaddition of a methylene group from N5,N10-methylenetetrahydrofolicacid, or oxidized to CO2 and NH3.
Cystine: This amino acid is reduced to cysteine, using NADH + H+as a reductant. Cysteine undergoes desulfuration to yield pyruvate.
Threonine: This amino acid is converted to pyruvate or to -ketobutyrate, which forms succinyl CoA.
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Amino acids that form fumarate
Phenylalanine and tyrosine: Hydroxylation ofphenylalanine leads to the formation of tyrosine. Thisreaction, catalyzed by phenylalanine hydroxylase, is the
first reaction in the catabolism of phenylalanine. Thus,the metabolism of phenylalanine and tyrosine merge,leading ultimately to the formation of fumarate andacetoacetate. Phenylalanine and tyrosine are, therefore,both glucogenic and ketogenic.
Inherited deficiencies: Inherited deficiencies in theenzymes of phenylalanine and tyrosine metabolism leadto the diseases phenylketonuria and alkaptonuria andthe condition of albinism
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Other amino acids that form succinyl CoA Degradation of valine, isoleucine, and threoninealso
results in the production of succinyl CoAa tricarboxylicacid (TCA) cycle intermediate and glucogeniccompound.
Valine and isoleucine: These amino acids are branched-chain amino acids that generate propionyl CoA, which isconverted to succinyl CoA by biotin- and vitamin B12requiring reactions
Threonine: This amino acid is dehydrated to -ketobutyrate, which is converted to propionyl CoA andthen to succinyl CoA. [Note: Threonine can also beconverted to pyruvate.]
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Catabolism of the branched-chainamino acids
The branched-chain amino acids, isoleucine,leucine, and valine, are essential amino acids. In
contrast to other amino acids, they aremetabolized primarily by the peripheral tissues(particularly muscle), rather than by the liver.Because these three amino acids have a similar
route of catabolism, it is convenient to describethem as a group
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Bi th i f N ti l
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Biosynthesis of Nonessential
Amino Acids
Nonessential amino acids are synthesizedfrom intermediates of metabolism or, as inthe case of tyrosine and cysteine, from the
essential amino acids phenylalanine andmethionine, respectively.
Some amino acids found in proteins, suchas hydroxyproline and hydroxylysine aremodified after their incorporation into theprotein
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Synthesis from -keto acids
Ala,Glutamate and Aspartate
Glutamate is synthesized from its' widelydistributed -keto acid precursor by asimple 1-step transamination reactioncatalyzed by glutamate dehydrogenase.
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Synthesis by amidation
Glutamine: This amino acid, which contains an amidelinkage with ammonia at the -carboxyl, is formed fromglutamate by glutamine synthetase. In addition toproducing glutamine for protein synthesis, the reaction
also serves as a major mechanism for the detoxificationof ammonia in brain and liver.
Asparagine: This amino acid, which contains an amidelinkage with ammonia at the -carboxyl, is formed fromaspartate by asparagine synthetase, using glutamine as
the amide donor. The reaction requires ATP, and, likethe synthesis of glutamine, has an equilibrium far in thedirection of asparagine synthesis
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Serine: This amino acid arises from 3-phosphoglycerate,
an intermediate in glycolysis which is first oxidized to 3-phosphopyruvate, and then transaminated to 3-phosphoserine. Serine is formed by hydrolysis of thephosphate ester. Serine can also be formed from glycinethrough transfer of a hydroxymethyl group by serinehydroxymethyl transferase.
Glycine: This amino acid is synthesized from serine byremoval of a hydroxymethyl group, also by serine
hydroxymethyl transferase Cysteine: This amino acid issynthesized by two consecutive reactions in whichhomocysteine combines with serine, formingcystathionine, which, in turn, is hydrolyzed to -ketobutyrate and cysteine.
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Tyrosineis formed from phenylalanine by phenylalaninehydroxylase. The reaction requires molecular oxygenand the coenzyme tetrahydrobiopterin (BH4), which canbe synthesized from guanosine triphosphate (GTP) by
the body. One atom of molecular oxygen becomes thehydroxyl group of tyrosine, and the other atom isreduced to water.
During the reaction, tetrahydrobiopterin is oxidized todihydrobiopterin. Tetrahydrobiopterin is regenerated
from dihydrobiopterin in a separate reaction requiringNADH. Tyrosine, like cysteine, is formed from anessential amino acid and is, therefore, nonessential onlyin the presence of adequate dietary phenylalanine.
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Phenylketonuria (PKU), caused by a deficiency of phenylalaninehydroxylase PKU is the most common clinically encountered inbornerror of amino acid metabolism (prevalence 1:15,000).Biochemically, it is characterized by accumulation of phenylalanine(and a deficiency of tyrosine).
Hyperphenylalaninemia may also be caused by deficiencies in any
of the several enzymes required to synthesize BH4, or indihydropteridine (BH2) reductase, which regenerates BH4 fromBH2. Such deficiencies indirectly raise phenylalanineconcentrations, because phenylalanine hydroxylaserequires BH4 as a coenzyme. BH4 is also required for tyrosinehydroxylase and tryptophan hydroxylase, which catalyze reactions
leading to the synthesis of neurotransmitters, such as serotonin andcatecholamines
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Neonatal screening and diagnosis of PKU: Earlydiagnosis of phenylketonuria is important because thedisease is treatable by dietary means. Because of thelack of neonatal symptoms, laboratory testing forelevated blood levels of phenylalanine is mandatory for
detection. However, the infant with PKU frequently hasnormal blood levels of phenylalanine at birth because themother clears increased blood phenylalanine in heraffected fetus through the placenta. Normal levels ofphenylalanine may persist until the newborn is exposedto 24 to 48 hours of protein feeding. Thus, screeningtests are typically done after this time to avoid falsenegatives. For newborns with a positive screening test,diagnosis is confirmed through quantitativedetermination of phenylalanine levels.
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Maple syrup urine disease Maple syrup urine disease (MSUD) is a rare (1:185,000),
autosomal recessive disorder in which there is a partialor complete deficiency in branched-chain -keto aciddehydrogenase, an enzyme complex that
decarboxylates leucine, isoleucine, and valine.Theseamino acids and their corresponding -keto acidsaccumulate in the blood, causing a toxic effect thatinterferes with brain functions. The disease ischaracterized by feeding problems, vomiting,
dehydration, severe metabolic acidosis, and acharacteristic maple syrup odor to the urine. If untreated,the disease leads to mental retardation, physicaldisabilities, and even death.
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Albinism
Albinism refers to a group of conditions in which a defectin tyrosine metabolismresults in a deficiency in theproduction of melanin. These defects result in the partialor full absence of pigment from the skin, hair, and eyes.Albinism appears in different forms, and it may be
inherited by one of several modes: autosomal recessive(primary mode), autosomal dominant, or X-linked.Complete albinism (also called tyrosinase-negativeoculocutaneous albinism) results from a deficiency oftyrosinase activity, causing a total absence of pigmentfrom the hair, eyes, and skin. It is the most severe formof the condition. In addition to hypopigmentation,affected individuals have vision defects and photophobia(sunlight hurts their eyes). They are at increased risk forskin cancer
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Alkaptonuria
Alkaptonuria is a rare metabolic diseaseinvolving a deficiency in homogentisic acidoxidase, resulting in the accumulation of
homogentisic acid. The illness has three characteristic symptoms:
homogentisic aciduria (the patient's urinecontains elevated levels of homogentisic acid,
which is oxidized to a dark pigment on standing,large joint arthritis, and black ochronoticpigmentation of cartilage and collagenous tissue