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Liver primary site of uptake Pyrimidine Purine

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Liver primary site of uptake Pyrimidine Purine Powered By Docstoc
					                                                               Human plasma protein: 7.5g/dl
  Liver: primary site of uptake                                Albumin (1/2 life, 14-18 d)
    20% for hepatic protein synthesis (14% remains in            Transport of nutrients, drugs, hormones
    liver, 6% plasma)                                          Transthyretin (pre-albumin) (1/2 life, 2 d), RBP (1/2
       Plasma proteins                                         life: 12 h), blood clotting proteins
       N-containing compounds
                                                               Globulins:
       Purine and pyrimidine bases
                                                                  1-globulins: some glycoproteins, HDLs
    57% catabolized in the liver                                  2-globulins: some glycoproteins, Hb, ceruloplasmain,
    23% released into circulation (primarily BCAAs)              prothrombin, VLDLs
                                                                  -globulins: Transferrin, LDLs
                                                                  -globulins: Immunoglobulin, antibodies




Glutathione: Cysteine, glysine, glutamate (Scavenger of free
radicals)
Carnitine: Lysine, methionine (Transport of FAs)                     Pyrimidine:
Creatine: Arginine, glysine, methionine (Energy in muscle)             Uracil
Carnosine: Histidine, -alanine (Nerve transmission)                    Cytosine
Choline: Serine (CNS)
                                                                       Thymine
Serotonin, nicotinic acid: Tryptophan
Catecholamines, thyroid hormones, melanin: tyrosine                  Purine
Taurine: Cysteine                                                      Inosine
Haem: Glysine                                                          Adenine
Bile acids: Glysine, taurine
                                                                       Guanine




                                                                                                                         1
     57% of AAs taken up by the liver                                     Energy
          Transamination                                                     Oxidation of 100g of proteins requires 5 mole O2,
          Deamination                                                        but liver consume ~3moles per day
                                                                                Extrahepatic oxidation (intestine, muscle, kidney)
          Carbon skeleton or            keto acids
                                                                                Partial oxidation
          Urea cycle
                                                                          Glucose
     Catabolism of all AAs, except BCAAs
                                                                          Ketone bodies
     Detoxification of ammonia to urea                                    Cholesterol
                                                                             Leucine: HMG CoA reductase
                                                                          Fatty acids




                                                                          Urea cycle (in the liver)
   >70% of AA carbons can be glucogenic:                                    Uses four high energy bonds
         Phenylalanine, tyrosine, Aspartate, Asparagine, Valine,
         Isoleucine, Methionine, Threonine, Arginine, histidine,            Urea derives 1N from ammonia, a second N from
         proline, glutamate, glutamine, Alanine, glycine, serine,           aspartate and carbon from CO2/HCO3-
         cysteine and tryptophan                                              >75% excreted into urine by the kidneys
   <30% of AA carbons can be ketogenic:                                       <25% secreted from the blood into the intestinal lumen
         Isoleucine, leucine, lysine, threonine, leucine, threonine and       (degraded by bacteria to NH3, recycled)
         phenylalanine
   Some glucogenic AA are also ketogenic:                                 Glutamine synthesis
         Isoleucine, phenylalanine, tyrosine, tryptophan                    The liver has a back-up system for excess NH4+
   Ketogenic only: Leucine                                                  (forms glutamine)




                                                                           Liver (23%) released into circulation (mainly
                                                                           BCAAs)
Tubular                      Renal cell                       Blood          BCAAs: Primarily taken up by skeletal muscle
fluid                        Glutamine                                          Insulin   Low plasma BCAAs   High muscle uptake
                                                                           Kidney
                                                                             Uses AAs to maintain acid-base balance
  NH4+            NH4+                        HCO3-           HCO3-          S-containing AAs sulfuric acid
                                                                             Metabolism of neutral AAs neutral end products (CO2
                                                                             + glucose) (NH4+, urine, HCO3-, blood)
                              Glucose
                                                                             Mainly glutamine, glycine




                                                                                                                                       2
                                                                                                              Major pathways for amino acid flow between tissues
                                                                                                                        POST-PRANDIAL PHASE
                                                                                                                                            Mixture of amino acids
                                                                                                                                            enriched in branched-
                                                               Diet adequate
                                                                                                                                                    chains
                                                               in protein    Optimum body
                                                                               protein nutrition is
                                                                               achieved when protein
                                                                               & EI (from CHO &                                                                                          Muscle
                                                                               lipids) are sufficient to                                Liver
  Nitrogen balance




                                                                               meet or balance the
                                                                               needs for AAs, N &
                                                                               EE
                                                                                                                                                                                          Adipose
                                                                                                                                                          Alanine                         Tissue
                                                                 Diet low in
                                                                 protein
                                                                                                                      Dietary     Alanine        Serine             Glutamine
                                                                                                                    amino acids



                                                                          A = low energy intake
                                                                                                                                                                                 Kidney
                                                                          B= high energy intake
                               A            B
                                     Energy intake                                                             Intestine




Major pathways for amino acid flow between tissues                                                         Major pathways for amino acid flow between tissues
            Postabsorptive state                                                                                              starvation

                                                                CO2                                                                                                 CO2
                                                                          energy                                                                                                energy
                        Protein                                                                                     Protein


                      AAs     Ala,                                                         O2                   AAs        Ala,                                                              O2
                              Gln                                                                                          Gln
                        CO2                          Glycogen                                                      CO2
                                                     Glucose            glucose         AAs                                                         Glucose

                                                     ketones                                                                                        ketones
                                   FFA                           urea                                                         FFA                                   urea



                       TG                glycerol                                                                                     glycerol
                                                                                                                 TG




 Biology of protein and amino acid requirement
                                                                                                            Support synthesis
   Body protein mass
                                                                                                            Maintenance of cell and protein content
   Turnover of protein and AA metabolism
                       Protein metabolism (synthesis, degradation, turnover)                                Body N increases rapidly from birth,
                     AAs as precursors of physiological important                                           childhood, early maturity (max 3rd decade).
                     nitrogen compounds                                                                     Thereafter decreases
                     Urea cycle enzymes and urea production
                       detoxification of ammonia




                                                                                                                                                                                                    3
                                                    Newborn           Adult
                Whole body (Kg)                                                              Metabolic systems responsible for the maintenance
                   Body weight                            3.5               70               of body protein & AA homeostasis:
                      Total Protein                      0.41               11                  Protein
                Tissue Protein (% total)                                                            Synthesis
                  Muscle                                  29                43                      Breakdown or degradation
                  Skin                                    21                15                  AAs
                  Blood                                                                             Interconversions, transformation & oxidation with the
                                                          19                16
                                                                                                    elimination of CO2 & urea production.
                  Liver                                   5                 1.8
                                                                                                    Synthesis (dispensable, conditionally indispensable)
                  Brain                                   6                 1.5
                  Kidney                                  1                 0.3




                       Balance in body protein by two endogenous N cycles

                                                                                               Body composition
                                                                       N intake
                Intake             Excretion                                                   Nitrogen balance
                                                                                               Whole body protein and amino acid kinetics
                                                          Protein
                                                        Breakdown         Body
                                                                                               Protein turnover in individual tissues
                                                                           N                   Limb and organ amino acid balance
            Synthesis              Degradation            Protein         pool
                                                         Synthesis                            techniques
                                                                                               Amino acid oxidation
                                                                     N excretion




                                                                                                      Protein turnover in the body
                                                                                       IN:    Protein intake                                    Protein synthesis
                              Protein synthesis
                                                                                                   90g
                                                                                                                                       Muscle              75g    (30%)
                              Protein degradation                                                            Secreted
                200                                                                                                                    Brain, lung etc     127g   (50%)
                                                                                                           protein (70g)
                                                                                                                                       Plasma proteins            (20%)
                                                                                                                                                 albumin   12g
Relative Rate




                                                                                                                                                 other     8g
                                                                                                               Absorbed
                                                                                                                (150g)                           WBC       20g
                                                                                                                                                 RBC       8g
                100                                                                                                                                        250g   (100%)



                 50                                                                                                        Urinary N     Other losses
                                                                                       OUT:    Fecal N
                                                                                                 10g                          75g             5g
                                                                                                1.6gN                        12gN           0.8gN

                          A            B            C       D         E            F




                                                                                                                                                                           4
    Permits
        Organisms to adjust to changes in the internal environment               Protein turnover:
        Tissue remodeling during growth and repair                                 Degradation & synthesis
        Selective removal of mutant, damaged and mis-folded                        4.6g/kg body weight
        proteins                                                                       70kg men: 320g daily
    Protein synthesis/degradation:                                                     Protein intake: 70g/day
        4-5kcal basal energy expenditure for each g of protein                   Plasma proteins:
        synthesis/turnover
                                                                                   High turnover
        Protein and AA metabolism: 20% of total BEE
    Thus, a relation between energy and protein                                  Liver and intestine:
    metabolism                                                                     50% of protein turnover
    Selectivity of protein turnover                                              Muscle (50% of protein):
                                                                                   25% of protein turnover




Name                                           EC number Liver half-   Protein Type    Name                                           EC         Liver half-
                                                         life (h)                                                                     number     life (h)
1.Ornithine decarboxylase                      4.1.1.17        0.2     Nuclear         RNA polymerase I                               2.7.7.6        1.3
2. Tyrosine aminotransferase                   2.6.1.5         2.0                     RNA polymerase II                              2.7.7.6        12
3. Tryptophan oxygenase                        1.13.11.11      2.5                     Histone                                                       432
4. HMG-CoA reductase                           1.1.1.34        3.0     Mitochondrial    -Aminolevulinate sunthetase (matrix)          2.3.1.37       1.1
5. Serine dehydratase                          4.2.1.12        4.0                     Ornithine oxo-acid aminotransferase (matrix)   2.6.1.13       19
6. Phosphoenolpyruvate carboxykinase           4.1.1.32        5.0
7. Glucokinase                                 2.7.1.2         12                      Alanine transaminase (matrix)                  2.6.1.2         20
8. Dihydroorotase                              3.5.2.3         12                      Glutamate dehydrogenase (matrix)               1.4.1.3         24
9. Glucose-6-phosphate dehydrogenase           1.1.1.49        15                      Monoamine oxidase (outer membrane)             1.4.3.4         55
10. Pyruvate kinase                            2.7.1.40        30                      Citrate synthase (matrix)                      4.1.3.7         94
11. Fructose-1,6-biphosphatase                 3.1.3.11        36                      Malate dehydrogenase (matrix)                  1.1.1.40        96
12. Histidase                                  4.3.1.3         60                      Glycerol-P dehyfdogenase (inner membrane)      1.1.99.5        96
13. Arginase                                   3.5.3.1         96
14. Aldolase                                   4.1.2.13        118                     Pyruvate decarboxylase (matrix)                6.4.1.1        110
15. Glyceraldehyde-3-phosphate dehydrogenase   1.2.1.12        130                     Cytochrome bc (inner membrane)                                132
16. Lactate dehydrogenase (isoenzyme 5)        1.1.1.27        144                     Cytochrome c oxidase (inner membrane)          1.9.3.1        134
                                                                                       Cytochrome c (inner membrane)                                 150
                                                                                       Carbamoyl phosphate synthetase (matrix)        6.3.4.16       185
                                                                                       Pyruvate dehydrogenase (matrix)                1.2.4.1        194




                                                                             High protein synthesis in young:
     Transcriptional phase                                                        Protein deposition (30%) and turnover

     Translational phase                                                     Rate of protein synthesis/breakdown:
                                                                                  1-1.15g of P/kg/day
        Initiation, elongation, termination
                                                                             Higher than requirement
     Post-translational events                                                    0.8g of P/kg/day
        Glycosylation, phophorylation, methylation,                               Thus, reutilization
        acylation                                                            The cost of protein synthesis (2.75 Kcal/g)
        Deamination, isoaspartyl, deimination                                     Minimal estimate 4 mol ATP/GTP per peptide: 0.67 kcal/g.
                                                                                  Allowing for ATP cost of transporting AA s: 0.86 kcal/g.
                                                                                  Allowing for ATP cost of synthesizing mRNA: 1.22 kcal/g.




                                                                                                                                                               5
                                                                                                                                                                         Ubiquintin
                                                                                                            Abnormal protein
                                                                                                                                                                         proteasome
                                        Protein
                                                                                    Protein                                                                              pathway
                                     synthesis (A)      Protein allowance
 Age group                          (g/kg per day)      (B) (g/kg per day)         Ratio A/B
                                                                                                            Short-lived normal proteins
 Infant (premature)                   11.3, 14                   ~3.0                 4.5

                                                                                                            Long lived normal proteins
 Child (15 mo)                             6.3                   1.3                  5
                                                                                                                                                                          Lysosomes
                                                                                                         Proteins of the endoplasmic reticulum
 Child (2-8 years)                         3.9                   ~1.1                 4
                                                                                                            Extracellular proteins surface receptors
 Adolescent (~13 years)                    ~5                    ~1.0                 5
                                                                                                                                                                        Mitocjondrial
                                                                                                                                                                        proteases
 Young adult (~20 years)                ~4.6                     0.75                 6                     Mitochondrial proteins




                                             Example of tracer
                                                                                                               [13N] Tracer (e.g. 15N-glycine)
  Whole body
          End-Product (EP) methods           [15N]glycine
          Precursor methods                  [13C]leucine/[13C] KlC
                                                                                                                                                         Protein
  Specific Proteins                                                                                                                                     synthesis
                                                                                                                            Active
          Bolus/constant infusion            [13C]leucine,[2H5]phenylalanine                                                                                                             Body
                                                                                                 Diet                         N
          Tracer studies                                                                                                                                                                protein
                                                                                                                             pool
  Region                                                                                                                                                 Protein
                                                                                                                                                       breakdown
          Constant infusion/biopsy           [2H5]phenylalanine
          Arteriovenus difference            [15N-1-13C]leucine
              tracer studies
                                                                                                                           Excretion
          Multiple isotope                   [2H3]leucine(iv), [1-13C]leucine (ig)                                         13NH
                                                                                                                                  3
              (iv/ig-splanchnic)
                                                                                                                           [13N] urea
iv: intavenous; ig: intragastric; KIC: -ketoisocaproate




                                                                                                   Tissue/        Body       Total protein     Fractional      Amount             Protein
             L-[1-13C] Leucine                                                                      organ         weight      content (g)    synthesis rate    (g/day)        synthesis (% of
                   tracer
                                                                                                                   (%)                          (%day)                         whole body)

                                 Leucine                                Protein
                                                                                                 Skeletal           40                4200         2                84                  28
                                 outflow                               synthesis                 muscle
                                                                                        Body     Stomach           0.25                26         43                11              3.6
Dietary           Plasma                         Intracellular
                                                                                       protein   Small               1                105         40                42                  14
intake            leucine                           leucine
                                                                                                 intestine
                                                                      Protein
                                 Leucine                                                         Colon              0.6                63          9                6                   2
                                                                    breakdown
                                  inflow
                                                                                                 Liver              2.5               263         20                53                  18
             Leucine oxidation
                                                                                                 Heart              0.5                53         5.2               3                   1
                  (13CO2)
                                                                                                 White cells                                      6.2
Leucine         Leucine     Leucine outflow for Leucine Leucine inflow from
            =             +                    =
flux            oxidation   protein synthesis    intake + protein breakdown




                                                                                                                                                                                                  6
                                                                                                              Normal concen-   Maximum            New synthesis
                                                                                         Protein              tration (g/l)    increase in 48 h   (g/kg per. 24h)
                                  Protein synthesis (% of control)
                                                                                         C-reactive protein         0.01             X1000               0.25
Treatment                                Liver                   Muscle
                                                                                         Serum amyloid A            0.01             X1000               0.25
Starvation (2 days)                       71                          47
Protein-free diet (9 days)                70                          27                  1-Acid                      1               X4                 0.1
                                                                                         glycoprotein
Diabetes                                  51                          41
                                                                                          1-   Antitrypsin            2               X4                 0.2
Malaria infection                         66                          49
                                                                                         Fibrinigen                   2               X4                 0.2
Turpentine injection                      116                         66
                                                                                         Heptoglobin                  2               X4                 0.2
Interleukin-1                             145                         68
                                                                                         Total                                                           1.2
Cancer                                    126                         56




                                                                                                 High protein meals provides many large
                        Insulin                   Protein
                                                 synthesis
                                                                                                 neutral AA that compete with tryptophan for
                                                                                                 brain uptake
High protein meal                                 Glucose utilization
                                                                                                 High CHO meals promote tryptophan uptake
                                                                                                 by the brain
                                                 Hepatic glucose
                     Glucagon                                                                       Serotonin synthesis is stimulated
                                                 production
                                                                                                    The effect is sedation and is actively sought

                                                 AA catabolism




                                                            Blood
                                   e      Phenylalanine        FFA
                                nin
                            ala
                         nyl              Tyrosine
Brain                 Phe rosine
                         Ty         n     Tryptophan
                                pha                                                             When brain serotonin levels are low, persons
                             pto
     Tryptophan          Try
                                                                                                seem to snack more on CHO. This has been
                          V
     Serotonine
                       L a li
                    Iso euc ne
                                         Albumin      Tryptophan                                called the Wurtman hypothesis (1989)
                       leu ine           Albumin      FFA
                          c in
                              e
                                         Albumin      Tryptophan                                Depression problems
                                         Albumin      FFA                                           Possible deficiency of serotonin
                                                                           Pancreas                     High CHO diets may correct
                                                            Glucose

                  Isoleucine             Isoleucine                              ul i
                                                                                     n              Possible deficiency of norepinephrine
                   Leucine                Leucine                          Ins
                                                                                                        Tyrosine loading may work if the problem is lack of or
                    Valine                 Valine
                                                            Insulin
                                                                                                        insensitivity to dopamine
         Muscle




                                                                                                                                                                    7
                                                                          Mucus secreted in the gut is disproportionately rich in
Several of the enzymes of amino acid catabolism have high                 threonine and cysteine:
values of Km so their activity increases sharply as the                      As much as 60% of the threonine requirement is for mucus synthesis.
concentration of substrate increases in the fed state                        This depletes tissue pools of these two AAs mixture that cannot be
                                                                             used for protein synthesis.
aminoacyl tRNA synthetases               Km = 1   50 µmol /L                 These surplus AAs are used as metabolic fuel.
                                                                          Cortisol induces gluconeogenesis and breakdown of
lysine-ketoglutarate reductase           Km = 18 mmol /L                  muscle protein.
phenylalanine hydroxylase                Km = 660 µmol /L                    It acts on the liver, not on the muscle.
                                                                             It induces tryptophan dioxygenase and tyrosine transaminase.
branched chain aminotransferase          Km = 4 mmol /L                      This depletes tissue pools of these two essential amino acids leaving
                                                                             an unbalanced amino acid mixture that cannot be used for protein
fasting liver amino acid concentrations    30 50 µmol /L                     synthesis.
There is irreversible loss of these amino acids as the                       These surplus amino acids are used as metabolic fuel.
concentrations rise above that at which aminoacyl tRNA
synthetases are saturated




                                                               DIETARY PROTEIN                  2H2O+2CO2                        lungs               2CO2
 In response to trauma, acutephase proteins are
 synthesized                                                    LIVER                           2H2CO3
 They are disproportionately rich in threonine and                 SAA
                                                                                                                   _
 cysteine                                                                                     2H+ + 2HCO3
                                                               SO4   -2     2H+
 This depletes tissue pools of these two AAs leaving                                           SO4-2 + 2Na+
 unbalanced AA mixture that cannot be used for
 protein synthesis.
 These surplus of AAs are used as metabolic fuel.                                                                                               2Na+
                                                                                                2Na2SO4                      KIDNEY                  2H+
                                                                                                                                                2HCO3-
                                                                                                       2NH3

                                                                                                                         URINE      (NH4)2SO4-2




 Krause s; Food , Nutrition and Diet Therapy (11th Edition)
 (2004). L.K. Mahan and S. Escot-Stump. W.B.Saunders
     Chapter 3

 Present Knowledge in Nutrition (8th Edition) (2001), B. A.
 Bowman and R. M. Russell. ILSI Press. Washington, DC.
     Chapter 5

 Human Nutrition and Dietetics (2000), J.S. Carrow, W.P.T
 James, A Ralph. Churchill Livingston.
     Chapter 6

 Introduction to Human Nutrition (2002). M. J. Gibney. H.H.
 Vorster and F. J Kok. Blackwell Science.
     Chapter 4




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