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DEGRADATION of THE CARBON SKELETON of AMINO ACIDS by 8TUgK1

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									 DEGRADATION
     of the
CARBON SKELETON
       of
  AMINO ACIDS
DEGRADATION of the CARBON SKELETON
of AMINO ACIDS:   OVERVIEW

  The carbon skeleton of amino acids are
  converted to:
1. CO2
2. Compounds that generate Glucose in the
     liver
    Pyruvate and TCA intermediates
    α-ketoglutarate, Succinyl CoA,
    Fumarate, and Oxaloacetate
3. Compounds that generate Ketone
     bodies or their precursors
    Acetoacetate, Acetyl CoA
DEGRADATION of the CARBON SKELETON
   of NON-ESSENTIAL AMINO ACIDS:
             OVERVIEW
 Non-essential amino acids
 synthesized from intermediates of
 glycolysis generate Pyruvate

 Non-essential amino acids
 synthesized from intermediates of
 TCA get reconverted to the same
 precursor intermediates
DEGRADATION of the CARBON SKELETON
    of ESSENTIAL AMINO ACIDS:
            OVERVIEW
 Some essential amino acids have
 carbon skeletons that are converted
 to Pyruvate or intermediates of TCA

   Trp produces Pyruvate via alanine
   Met, thr, val, and Ile form Succinyl CoA
   Phe forms Fumarate after conversion to
   Tyr
DEGRADATION of the CARBON SKELETON
         of AMINO ACIDS:
            OVERVIEW

 Some amino acids have carbons
 that produces both Glucose and
 Ketone bodies

 One amino acid Leucine is
 exclusively ketogenic
  GLUCOGENIC   GLUCOGENIC/     KETOGENIC
Alanine
                KETOGENIC

Asparagine     Tyrosine
Aspartate
Cysteine
Glutamate
Glutamine
Glycine
Proline
Serine
               Isoleucine      Leucine
Arginine
               Lysine
Histidine
               Phenylalanine
Methionine
               Threonine
Valine
               Tryptophan
 METABOLIC DISORDERS of AMINO
       ACID METABOLISM

Generally caused by mutations in the
genes encoding the enzymes in the
AA metabolic pathway
Expressed as either a total loss or
partial loss of catalytic activity
Inherited disorders in AA metabolism
in the absence of treatment lead to
mental retardation or other
developmental abnormalities or
death
          GLYCINE DEGRADATION


                  H2C – NH3+

                       COO-
                  Glycine
                 FH4      NAD+
                                   Glycine cleavage
                                       enzyme
   N5, N10 – CH2-FH4      NAD+H


          CO2 +        NH4+    +   H+


* Major pathway in humans
      GLYCINE DEGRADATION

                                COO-
                                COO-
                                Oxalate
             O2
                  H2O
                        NH4+
                                      O2
              D-AA
H2C – NH3+   Oxidase H – C = O             CO2
                                           +
  COO-                         COO-
                                           H20
 GLYCINE                GLYOXYLATE


              PLP
  PYRUVATE          ALANINE
NON-KETOTIC HYPERGLYCINEMIA

Deficient enzyme:
Glycine cleavage        Glycine
enzyme


S/S:
 Severe mental
 retardation        CO2 + NH4+ + H+
              SERINE DEGRADATION

         Serine Hydroxymethyltransferase

  CH2 – OH              Methylene H4
               FH4          Folate
                                       H2C – NH3+
H–C–   NH3+
                                            COO-
  COO-
 Serine                                  GLYCINE

              Serine Dehydratase
  H20
              PLP
       NH4+

                O
                            PYRUVATE
         CH3 – C –   COO-
          SERINE DEGRADATION (con’t)

                                              CH2
    CH2 – OH
                      Pyruvate      Alanine   C=O
H – C – NH3+
                                              COO-
    COO-                      PLP         Hydroxypyruvate
     Serine                                      NAD+


                                                 NADH
              CH2OH
                                    ADP        COO-
   P -O–C–H             ATP
                                           H – C – OH
               COO-
                                               CH2OH
   2- Phosphoglycerate
                                           Glycerate


              PEP             PYRUVATE
               THREONINE DEGRADATION

                 NH3+                  H3C           S ~ CoA
   H3C – CH – CH - C – O-                        C
          OH          O
                                                 O Acetyl CoA
          Threonine
                                      CoASH          ATP

               Threonine Aldolase                    THIOKINASE
Glycine
                                           H2O       ADP

    H3C         H2O     NAD+   NADH + H+   H3C        O-
          CH                                     C
                  Aldehyde Dehydrogenase
        O                                        O
   Acetaldehyde                             Acetate
    CYSTEINE DEGRADATION
  A. Cysteine Sulfinate Pathway
      -OOC – CH – CH2 - SH
                  NH3+
         CYSTEINE
           O2            Cysteine dioxygenase


       -OOC – CH – CH2 - SO2-
                  NH3+
      Cysteine sulfinic acid
           α-KG
                    PLP         PAPS
           Glu
                                    ATP
Pyruvate
                SO2-            SO4       Urine
                                Sulfate
      CYSTEINE DEGRADATION
  B. 3-Mercaptopyruvate Pathway
            -OOC – CH – CH2 - SH
                   NH3+
              CYSTEINE
                        α-KA
   Transaminase        PLP
                       α-AA
                   O
             H 2 C – C – C – O-   3-Mercaptopyruvate
             HS        O
                           NAD+
       2H
                                    NADH + H+
            H2S
Pyruvate                       3-Mercaptolactate
   DISORDERS of CYSTEINE
       METABOLISM

Homocystinuria         Cystathioninuria
 Deficiency of         Deficiency of
 cystathionine         Cystathionase
 synthase
                       No clinical
 ↑ homocysteine in
 urine
                       problems noted
 Met and metabolites   ↑ cystathionine
 are ↑ in plasma       and metabolites
 S/S: Mental           in plasma and
 retardation, lens
 dislocation and
                       urine
 osteoporosis
      HYDROXYPROLINE DEGRADATION

        H        Hydroxyproline DH
  H         H
            N+ - H                          N+ - H
   OH                                  OH
                             H2              C – O-
            C – O-
        O                                    O
Hydroxyproline           Δ1-Pyrroline –Hydroxy-5-Carboxylase

                                            Spontaneous

                              OH         NH3+
                        HC – CH – CH2 – CH – C – O-
                         O                   O


                     Hydroxy-glutamate semialdehyde
HYDROXYPROLINE DEGRADATION (con’t)

          OH          NH3+
     HC – CH – CH2 – CH – C – O-
      O                     O

   Hydroxy-glutamate semialdehyde

              NAD+   H2O
                        Dehydrogenase

      NADH + H+

               OH          NH3+
     O – C – CH – CH2 – CH – C – O-
          O                       O

     Erythro-hydroxy- glutamate
  HYDROXYPROLINE DEGRADATION (con’t)

                     OH          NH3+
             O – C – CH – CH2 – CH – C – O-
                 O                      O

             Erythro-hydroxy-glutamate
 Transaminase             α-KA

                     α-AA                          Glyoxylate
        OH           O

O – C – CH – CH2 – C – C – O-               Aldolase

    O                     O

                                                   Pyruvate
α-Keto-hydroxyglutarate
         TRYPTOPHAN DEGRADATION
                                      NH3+
                              -CH2 – CH – COO-

                                 Tryptophan
                          N



                              HCOO-   Formate
                    Kynurenine
Xanthurenic acid    PLP   Kynureninase
and other urinary
metabolites
                              Alanine            Pyruvate

Nicotinamide moiety
of NAD and NADP                  Acetyl CoA
    TRYPTOPHAN DEGRADATION


Hartnup Disease

Impaired intestinal and renal
reabsorption of Tryptophan and
other neutral amino acids
Pellagra-like symptoms
  ARGININE DEGRADATION


H2N                  NH
                                    Arginine
  C - NH – CH2 – CH2 – CH – COO-
  NH+
           H2O
                   ARGINASE

         UREA
                    NH
 NH3+ – CH2 – CH2 – CH – COO-      Ornithine
          α-KG
                  Ornithine σ-aminotransferase

      Glutamate                    Glutamate
Glutamate semialdehyde
                                α-Ketoglutarate
  GLUTAMINE and GLUTAMATE DEGRADATION



    O         *GLUTAMINASE   O                    O
    C - NH2                               AST
                             C–O                  C–O
    CH2         H2O   NH4+ CH2      PYR     ALA   CH2
    CH2                      CH2                  CH2
 H – C – NH3+           H - C - NH3+      PLP     C=O
    COO-                     COO-                 COO-


Glutamine              Glutamate           α-Ketoglutarate


*GLUTAMINASE: Excretion of acids by the kidneys
             HISTIDINE DEGRADATION

                                 N-Formiminoglutamate
           HN       NH               (FIGLU)
    H3N+
                                               HN   N+H2
O - C – CH – CH2
                            O – C – CH2 – CH2 – CH – C – O-
   O
                                O                     O
    Histidine                          Imidazole propionate
                                       hydrolase
           HISTIDASE
                                               HN         NH
NH4+
            HN       NH H2O
                                                          O
                                     O - C – CH2 – CH2
  O - C – CH = CH
                         UROCANASE      O
       O
                                4-Imidazole-5-propionate
   Urocanate
          HISTIDINE DEGRADATION (con’t)

                              HN   N+H2
            O – C – CH2 – CH2 – CH – C – O-
                 O                   O
             H4 Folate   N-Formiminoglutamate (FIGLU)

                         Glutamate Formimino Transferase
N5-Formimino H4 Folate


                L - Glutamate




                α-KETOGLUTARATE
      HISTIDINE DEGRADATION



Folic acid deficiency: FIGLU is
excreted in the urine

Test dose with Histidine can be
used to detect Folic acid
deficiency
                         PROLINE DEGRADATION
 H2C          CH2
                                    α-Ketoglutarate
                                                       NH3+
  H 2C            CH – COO-
                                  -OOC   – CH2 – CH2 – CH – COO-
         N
                                           Glutamate
         H2
   PROLINE                        NADH + H+
 NAD+                                            GLUTAMATE
                                                 SEMIALDEHYDE DH
              PROLINE DH
                                        NAD+
NADH2                                                NH3+
   H2C             CH2           H – C – CH2 – CH2 – CH – COO-
                                    O
    HC             CH – COO-       Glutamate semialdehyde
              N
              H
Δ1-Pyrroline 5-carboxylate
ASPARTATE and ASPARAGINE DEGRADATION

                                      COO-
     COO-
                                      CH2
     CH2               PLP
                                   H – C – NH3+
     C=O
                       AST             COO-
     COO-
 Oxaloacetate                        Aspartate
                             H20
                O
                C – NH2               Asparaginase

                CH2
            H – C – NH3+
                COO-
            ASPARAGINE
                  SUCCINYL CoA DERIVATIVES

                              Methionine
                                                          Met adenosyl
N5 - CH3- FH4      B12                       AdoMet
                                                          transferase
                                                   CH3
                                       S-Adenosyl homocysteine
                B12-CH3
                             Homocysteine
                          Serine
                                      PLP
                             Cystathionine
                     Cysteine         PLP
   Threonine                 α-Ketobutyrate
                                                   Isoleucine
 Threonine          NH3               CO2          Acetyl CoA
 dehydratase
                             Propionyl CoA
                                                   Valine
                             Biotin

                                             B12
                                                      SUCCINYL CoA
 BRANCHED-CHAIN AMINO ACID DEGRADATION

    Valine                     Isoleucine              Leucine

TRANSAMINATION             TRANSAMINATION            TRANSAMINATION

                           α-Keto β-methylvalerate   α-Ketoisocaproate
 α-Ketoisovalerate

              CO2                        CO2                     CO2
   *                            *                      *
             NADH                      NADH                   NADH
                           2-Methylbutyryl CoA       Isovaleryl CoA
Isobutyryl CoA
                                                              FADH2
                                        2 NADH
 FADH2
                     CO2                Acetyl CoA
                           Propionyl CoA
                                                      HMG-CoA
          2 NADH


                                                     Acetoacetate
                           SUCCINYL CoA
BRANCHED-CHAIN AMINO ACID DEGRADATION


 *Branched-chain α-ketoacid Dehydrogenase
 Multimeric enzyme complex
   Decarboxylase
   Transacylase
   Dihydrolipoyl dehydogenase
 Regulation: Covalent modification
   Inactive when phosphorylated
   Active when dephosphorylated
 MAPLE SYRUP URINE DISEASE

Deficiency of     High mortality
Branched chain
α-Keto acid       Neurologic
dehydrogenase     problems very
↑ Levels of       common
BCAAs and their
α-keto
analogues in      BC ketoacidosis
plasma and        Severe mental
urine             retardation
PHENYLALANINE and TYROSINE DEGRADATION
                   Phe Hydroxylase
                NH3+                                    NH3+
        CH2 – CH – COO-                         CH2 – CH – COO-
                                  HO

                                                    Tyrosine
                            PKU
                                                       TAT
Phenylalanine                          PLP
                                                     Tyrosinemia II
                                   CH2 – CH – COO-

                       HO                 O

                                    p-Hydroxyphenylpyruvate



                                   OH

                                       CH2 – COO-


                          HO        Homogentisate
  PHENYLALANINE and TYROSINE DEGRADATION
                              (con’t)
                                 OH

                                  CH2 – COO-    Homogentisate

                         HO    [O]
          Alkaptonuria                  Homogentisate Oxidase
                               Fe2+
                  Maleylacetoacetate



                  Fumarylacetoacetate

         Tyrosinemia I           Fumaryl acetoacetate Hydrolase


-OOC – CH = CH – COO-                    CH3 – CO – CH2 – COO-

     Fumarate                              Acetoacetate
   HYPERPHENYLALANINEMIAS

PKU is caused by the
deficiency of Phe        Phenylalanine
hydroxylase
Most commonly          Phe
                                     BH4
encountered Inborn     hydroxylase

error of metabolism
Also caused by
deficiencies of the         Tyrosine
enzymes that
synthesize
Tetrahydrobiopterin
     HYPERPHENYLALANINEMIAS


Tetrahydrobiopterin (BH4) is also required
for tyrosine and tryptophan hydroxylases
for Catecholamine and Serotonin synthesis
Aspartame: dipeptide of glutamate and
methylphenylalanine
Dietary restriction of Phenylalanine does
not reverse the CNS effects due to
neurotransmitter deficiencies
  Need to administer serotonin and
  catecholamine precursors
HYPERPHENYLALANINEMIAS

Elevated levels of   CNS symptoms
Phe in plasma and     Mental
urine                 retardation
Elevated levels of    Failure to walk
phenylketones         and talk
(phenylacetate,       Seizures
phenyllactate, and
                      Hyperactivity
phenylpyruvate)
giving the “mousy     Microcephaly
odor”                 Failure to grow
                      Tremors
                 ALTERNATIVE PATHWAYS
        for PHENYLALANINE DEGRADATION
                                     CH2 – CH – COO-
                                           NH3+

                      α-KG                                 Tyrosine
                                             CH2 – COO-
                      Glu
        CH2 – CH – COO-      H20   CO2
             O                                    Phenylacetate
                            NAD+   NADH
         Phenylpyruvate                     GLUTAMINE
NADH2                                                          COO-

NAD+     CH2 – CH – COO-                      CH2 – C –NH - CH

                 OH                                    O       CH2
                                                                CH2
            Phenyllactate
                                            Phenylglutamine CONH2
            ALBINISM

Defective Cu+-        Tyrosine
dependent tyrosine
hydroxylase of the
Melanocytes
Lack of pigments in
the skin, hair, and
eyes
↑ predisposition to   Melanin
skin CA
Photophobia
            ALCAPTONURIA
Defective enzyme:
Homogentisate                     Tyrosine
oxidase
Homogentisate, an
intermediate of Tyrosine       Homogentisate
metabolism can not be
further oxidized
Homogentisate auto-          Maleylacetoacetate
oxidizes forming dark
pigments to discolor
urine                       Fumarylacetoacetate
Chronic deposits in the
cartilage and joints,
leading to arthritis and   Acetoacetate + Fumarate
Oochronosis
           TYROSINEMIAS

Tyrosinemia I
                               Tyrosine
Genetic deficiency of
Fumarylacetoacetate     Hydroxyphenylpyruvate
hydrolase
Hepatorenal form:          Homogentisate
Liver failure and
early death
Hypertension, Acute
tubular dysfunction,
rickets,                Fumarate + Acetoacetate
polyneuropathy
          TYROSINEMIAS

Tyrosinemia II               Tyrosine
(Richner-Hanhart
Syndrome)             Hydroxyphenylpyruvate

Deficiency of            Homogentisate
Tyrosine
aminotransferase
Oculocutaneous form
with eye and skin
lesions
                      Fumarate + Acetoacetate
Neurologic problems
Mental retardation
                     LYSINE DEGRADATION

    L- Lysine                               Crotonyl CoA
            NADH + H+                               NAD+
 α-KG
        *               CO2 + Acetyl CoA
                                                    NADH + H+
            NAD+                             Glutaryl CoA
  Saccharopine                                      CO2

             NAD+
                                                     CoASH
            *                                α-Ketoadipate
Glutamate       NADH + H+                            α-KG


  L-α-Aminoadipate-δ-       NADH2   NAD+             Glu
     semialdehyde
                                           L- α-Aminoadipate


 * Aminoadipate semialdehyde synthase
    OVERVIEW: DEGRADATION of AMINO ACIDS
Tryptophan                                              ARGININE
               Alanine
                                                        HISTIDINE
               Serine
Glycine                                                 GLUTAMINE
               Cysteine      PYRUVATE                   PROLINE
 THREONINE     OHproline

                          OXALOACETATE          GLUTAMATE
   ASPARTATE
   ASPARAGINE
                                   KREB’S
                          MALATE          α-KG
                                   CYCLE
 ASPARTATE
                          FUMARATE
 TYROSINE                                SUCCINYL CoA
 PHENYLALANINE                                    B12
                         VALINE          METHYLMALONYL CoA
                         THREONINE
                                                  Biotin
                         ISOLEUCINE
                                         PROPIONYL CoA
                         METHIONINE
OVERVIEW: DEGRADATION of AMINO ACIDS

                                   Isoleucine
                                   Leucine
                  PYRUVATE         Tryptophan


                                  ACETYL CoA

       OXALOACETATE
                                  ACETOACETATE
        MALATE   KREB’S
                 CYCLE α-KG         Leucine
       FUMARATE    SUCCINYL CoA     Lysine
                                    Phenylalanine
                                    Tryptophan
                                    Tyrosine
    KETOGENIC AMINO ACIDS

                                 Leucine




Acetyl CoA + Acetoacetyl CoA     HMG CoA


  Thr                          Acetoacetate
  Leu
  Lys
  Ile
                                Phe, Tyr
  Trp
REFERENCES:
1. Harper’s Biochemistry 25th and
           THANK YOU!
 27th Eds.
2. Devlin’s Biochemistry with Clinical
 Corrleation, 4th Ed.
3. Leninger, Principles of
 Biochemistry: 4th Ed., 2005.
4. Mark’s Clinical Biochemistry, 2004.

								
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