OVERVIEW OF AMINO ACID METABOLISM ENVIRONMENT ORGANISM Ingested protein Bio- synthesis Protein AMINO ACIDS Nitrogen Carbon skeletons Urea Degradation (required)

OVERVIEW OF AMINO ACID METABOLISM

ENVIRONMENT ORGANISM

Ingested protein

Bio- synthesis Protein

AMINO ACIDS

Nitrogen Carbon

skeletons

Urea

Degradation (required)

1 2 3

a

b

PurinesPyrimidinesPorphyrins

c c

Used for energy

pyruvateα-ketoglutaratesuccinyl-CoAfumarateoxaloacetate

acetoacetateacetyl CoA

(glucogenic)(ketogenic)

A m in o A c id R e q u ir e m e n t s o f H u m a n s - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - N u t r i t io n a l ly E s s e n t ia l N u t r i t io n a l ly N o n e s s e n t ia l - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - -

A r g in in e a A la n i n e H is t id i n e A s p a r a g i n e I s o le u c in e A s p a r ta te L e u c in e C y s te i n e L y s i n e G lu ta m a te M e th io n in e G lu ta m i n e P h e n y la la n i n e G l y c i n e T h r e o n in e P r o l in e T r y p to p h a n S e r in e V a l in e T y r o s in e

- - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - a “ N u tr i t io n a l l y s e m ie s s e n t ia l .” S y n t h e s iz e d a t r a te s in a d e q u a te to s u p p o r t g r o w t h o f c h i ld r e n .

NITROGEN BALANCE

Nitrogen balance = nitrogen ingested - nitrogen excreted

(primarily as protein) (primarily as urea)

Nitrogen balance = 0 (nitrogen equilibrium)

protein synthesis = protein degradation

Positive nitrogen balance

protein synthesis > protein degradation

Negative nitrogen balance

protein synthesis < protein degradation

TRANSAMINATION

UREA CYCLE

mitochondria

cytosol

Function: detoxification of ammonia (prevents hyperammonemia)

FATE OF THE CARBON SKELETONS

Carbon skeletons are used for energy.

Glucogenic: TCA cycle intermediates

or pyruvate (gluconeogensis)

Ketogenic: acetyl CoA, acetoacetyl CoA,

or acetoacetate

Purine and

Pyrimidine Metabolism

Major Bases

Source of each atom in the purine ring

N

N

N

N

9

1 8

7 6

5

4

3

2

Glycine

N10-Formyl-FH4

N10-Formyl-FH4

Aspartate (amine)

CO2

Glutamine (amide)

Ribose-5-phosphate

5-Phosphoribosyl-1-pyrophosphate (PRPP)

⊖ ⊕ ⊖ ⊖

5-Phosphoribosylamine

IMP

Adenylosuccinate XMP

AMP GMP

⊖⊖

Summary and Regulation

Inhibition of Purine Biosynthesis by the Antitumor Agent, 6-Mercaptopurine

1) 6-Mercaptopurine is converted to a nucleotide.

2) The nucleotide inhibits purine biosynthesis at steps 2, 12a, 12b, and 13a.

Major Bases

Cytosine (C) Uracil (U) Thymine (T)

N

N

2

1

3

4

5

6

Aspartate

CO2

Glutamine

Sources of the atoms of the pyrimidine ring:

DNA and RNA Degradation

“Salvage Pathway” for Purines(~90%)

Lesch-Nyhan Syndrome

Degradation of Purines(~10%)

AllopurinolInhibits xanthine oxidase

X

X

Heme

N

Pyrrole

Structure

Porphyrias

hemoglobin

globinheme

free amino acids

degraded (bilirubin)

Fe (reutilized)

Heme

Biliverdin

Unconjugated bilirubin

Reticuloendothelial system

Unconj.bilirubin/albumin complex

Systemic circulation

HepatocytesUnconj. bilirubin

Bilirubin diglucuronide

Small intestineLarge intestine

Bilirubin diglucuronide

BilirubinUrobilinogenStercobilins

Kidney

urine

HYPERBILIRUBINEMIA

-- elevated bilirubin in serum (above 1 mg/dL)

-- can be conjugated or unconjugated or both depending on the situation

-- elevated bilirubin can diffuse into tissues, making them appear yellow (jaundice)

HYPERBILIRUBINEMIA

Clinical Consequences:

-- Conjugated hyperbilirubinemia: benign

-- Unconjugated hyperbilirubinemia: benign at concentrations < 25 mg/dL (albumin capacity)

-- At concentrations >25 mg/dL, unconjugated bilirubin is free (uncomplexed) and can enter the brain.

bilirubin encephalopathy (kernicterus)

Causes of JAUNDICE

1) Hemolytic anemia

-- destruction of erythrocytes

2) Hepatitis or cirrhosis

-- conjugation and excretion of bilirubin

3) Bile duct obstruction

-- conjugated bilirubin not delivered to intestine;

it backs up, spills over into the blood4) Neonatal “physiological jaundice”

-- immature hepatic system of the newborn:

uptake, conjugation, excretion of bilirubin