Ammonia and Inter-Organ Relationships

Question 1

What is the interorgan relationship between peripheral tissues, liver, and muscle in regards to nitrogen removal/fixation?

Answer 1

Liver:

• glutamine -> glutamate -> NH4+ -> urea

Peripheral Tissues:

• amino acids -> glutamate (OR -> NH4+) -> glutamine -> liver, kidney

Kidney:

• glutamine -> glutamate + NH4+ -> urine

Muscle:

amino acids -> glutamate -> alanine -blood-> alanine (liver) -> pyruvate (liver) -> glucose (liver) -blood-> glucose (muscle) -> pyrivate (muscle) -> alanine

Question 2

What are the complex arrays of specific metabolic pathways involved in the fate of carbon skeletons of amino acids?

Answer 2

carbon skeletons of amino acids are alpha-keto acids

all carbon skeleton breakdown pathways converge to form 7 intermediates:

• oxaloacetate
• alpha-ketoglutarate
• pyruvate
• fumarate
• succinyl CoA
• acetyl CoA
• acetoacetyl CoA

Question 3

What are the seven intermediates of carbon breakdown pathways used for?

Answer 3

synthesis of glucose, lipids, or ketone bodies

energy production by complete oxidation to CO2 and water via TCA cycle

• excess amino acids
• starvation conditions
• low carbohydrate diet

Question 4

What are the three kinds of amino acids?

Answer 4

Ketogenic amino acids

Glucogenic amino acids

Mixed amino acids

Question 5

What are ketogenic amino acids?

Answer 5

only provide acetyl CoA or acetoacetyl CoA (no net glucose synthesis)

leucine and lysine - ketogenic only

recall can produce ketone bodies from acetyl CoA

‘ketones in lieu of lysine’

Question 6

What are glucogenic amino acids?

Answer 6

yields any of the other products of ketogenic amino acids (except acetyl CoA and acetoacetyl CoA)

because provides more than just the 2 carbon acetyl CoA, can provide a net yield of glucose

18 of the amino acids are glucogenic (all except leucine and lysine)

Question 7

What are mixed amino acids?

Answer 7

yields products that are both ketogenic and glucogenic

isoleucine, phenylalanine, threonine, tryptophan, tyrosine - the mixed amino acids

Question 8

What are inborn errors of metabolism?

Answer 8

caused by mutant genes that cause production of abnormal protein (enzyme)

total loss of enzyme activity or partial deficiency in catalytic activity

usually a food product is not metabolized -> build up in body -> symptoms

may lead to mental retardation or other developmental abnormalities if not controlled

diet changes may control disease - early diagnosis very important

Question 9

What is phenylketonuria (PKU)?

Answer 9

caused by a deficiency of phenylalanine hydroxylase (PAH) caused by mutations in PAH gene

Question 10

What are the biochemical symptoms of PKU?

Answer 10

accumulation of phenylalanine (hyperphenylalanemia) [note: PAH requires BH4 as a coenzyme; hyperphenylalanemia may be caused by deficiencies in enzymes required to synthesize BH4 or in dihydropteridine reductase (regenerates BH4 or BH2)]

deficiency in tyrosine

Question 11

What are the characteristics of classic PKU?

Answer 11

high concentration of phenylalanine (10x normal) in tissue, plasma and urine [elevated phenyllactate, phenylacetate, and phenylpyruvate -> give urine a musty (mousey) odor]

CNS symptoms: severe intellectual disability, developmental delay, microcephaly, and seizures

Hypopigmentation: fair hair, light skin color, and blue eyes

Question 12

What are the treatments of PKU?

Answer 12

restrict phenylalanine in diet -> feed synthetic amino acid preparations free of phenylalanine supplemented with some natural foods (fruits, vegetables, and certain cereals) with lo phenylalanine count -> keep blood phenylalanine level close to normal range

early treatment is important to prevent neurologic damage (during first 7-10d of life)

must supplement tyrosine in the diet (becomes an essential amino acid for these patients)

Question 13

What is alkaptonuria?

Answer 13

caused by deficiency in homogentisate oxidase

rare metabolic condition

accumulation of homogentisate

Question 14

What are the characteristic symptoms of alkaptonuria?

Answer 14

homogentisic aciduria -> elevated levels of homogentisate in urine -> oxidize to dark pigment on standing

large joint arthritis

deposition of black pigment in cartilage and collagenous tissue (ochronosis)

usually asymptomatic until 40

not life-threatining but arthritis may be severely crippling

Question 15

What is the treatment of alkaptonuria?

Answer 15

diet low in phenylalanine and tyrosine -> reduce levels of homogentisate and decrease pigment deposit in body tissues

Question 16

What is maple syrup urine disease (MSUD)?

Answer 16

rare autosomal recessive disorder

symptoms: feeding problems, vomiting, ketoacidosis, changes in muscle tone, neurological problems, maple-syrup like odor in urine
treatment: synthetic formula that is free of branched-chain amino acids supplemented with low levels of leucine, isoleucine, and valine [fatal if untreated]

Question 17

What is the prenatal diagnosis for PKU?

Answer 17

classic PKU caused by more than 100 different mutations in the phenylalanine hydroxylase (PAH) gene

prenatail diagnosis available if family history and disease causing mutation in the family identified

sample obtained by amniocentesis or chorionic villus sampling

sequence analysis, mutation analysis, duplication/deletion analysis or by using restriction fragment length polymorphism (RFLP)

Question 18

What is the prenatal diagnosis for maple syrup urine disease?

Answer 18

caused by mutation in one of the following three genes: BCKDHA, BCKDHB, or DBT

sample obtained by amniocentesis or chorionic villus sampling

prenatal diagnosis by measuring enzyme activity in cultured cells or by measuring branch-chain amino acid concentration in the amniotic fluid

if family history and disease causing mutation identified may also use mutation analysis

Question 19

What options are there for newborn screening?

Answer 19

screen for serious developmental, genetic, and metabolic disorders so that they can be treated before symptoms develop

although some conditions are rare, they are treatable if diagnosed early

blood sample obtained from heel prick betwen 1-7d of birth and screened using tandem mass spectrometry

screening only - need additional testing to confirm or rule out disorder

PKU screen mandatory in all states