Ammonia and Inter-Organ Relationships Flashcards
What is the interorgan relationship between peripheral tissues, liver, and muscle in regards to nitrogen removal/fixation?
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
What are the complex arrays of specific metabolic pathways involved in the fate of carbon skeletons of amino acids?
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
What are the seven intermediates of carbon breakdown pathways used for?
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
What are the three kinds of amino acids?
Ketogenic amino acids
Glucogenic amino acids
Mixed amino acids
What are ketogenic amino acids?
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’
What are glucogenic amino acids?
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)
What are mixed amino acids?
yields products that are both ketogenic and glucogenic
isoleucine, phenylalanine, threonine, tryptophan, tyrosine - the mixed amino acids
What are inborn errors of metabolism?
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
What is phenylketonuria (PKU)?
caused by a deficiency of phenylalanine hydroxylase (PAH) caused by mutations in PAH gene
What are the biochemical symptoms of PKU?
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
What are the characteristics of classic PKU?
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
What are the treatments of PKU?
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)
What is alkaptonuria?
caused by deficiency in homogentisate oxidase
rare metabolic condition
accumulation of homogentisate
What are the characteristic symptoms of alkaptonuria?
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
What is the treatment of alkaptonuria?
diet low in phenylalanine and tyrosine -> reduce levels of homogentisate and decrease pigment deposit in body tissues
What is maple syrup urine disease (MSUD)?
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]
What is the prenatal diagnosis for PKU?
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)
What is the prenatal diagnosis for maple syrup urine disease?
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
What options are there for newborn screening?
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
