Which amino acids are classified as ketogenic and which are classified as glucogenic?
purely ketogenic: leucine and lysine (both are essential)
purely glucogenic: glycine, alanine, serine, cysteine, valine, methionine, aspartate, arginine, histidine, glutamine, proline, glutamate
bothies: threonine, tryptophan, tyrosine, phenylalanine, isoleucine
Essentials: PVT TIM HALL --- phenylalanine, valine, tryptophan, threonine, isoleucine, methionine, histidine, arginine, leucine, lysine. phenylalanine, valine, tryptophan, threonine, isoleucine, methionine, histidine, arginine, lysine, leucine.
BCAAs = Valine, isoleucine and leucine
MAPLE SYRUP URINE DISEASE (MSUD) (branched-chain ketoaciduria)
--caused by a deficiency of the metabolic enzyme branched-chain α-keto acid dehydrogenase (BCKDH)
--can't break down BCAA's, several pathways blocked
--VAL --/-->SUCCINYL COA --> GLUCOSE
--ISO --/--> ACETYL CoA --> FATTY ACIDS
--ISO --/--> PROPIONYL COA --> GLUCOSE
--LEU --/--> ACETYL CoA
--ENZ NEEDS same 5 cofactors as PyruvateDHcomplex: TPP, NADH, FADH2, lipoic acid, & CoA
--autosomal recessive metabolic disorder, a type of organic acidemia
--Valine, isoleucine and leucine are all branch chain aas, BCAA's for short
--Valine and isoleucine are glucogenic, isoleucine and leucine are ketogenic
--children born with this defect die at about one year if untreated.
--affects approximately 1 out of 180,000 infants
--much higher prevalence in Amish & Mennonite kids (founder effect!?), (1:200 births!?)
--enz deficiency --> buildup of BCAA's and their toxic by-products in the blood and urine
--infant seems healthy at birth but can suffer severe neurologic damage, death
--S/Sx: sweet-maple-smelling urine, poor feeding, vomiting, dehydration, lethargy, hypotonia, seizures, ketoacidosis, and neurological decline.
METHYLMALONYL ACIDURIA
Methylmalonyl aciduria is caused by a defect in methylmalonyl CoA mutase. Vitamin B12 is required as a cofactor for methylmalonyl CoA mutase. Methylmalonyl CoA is a common intermediate in amino acid catabolism. Propionyl CoA requires biotin. Vitamin B12 is required two times in the amino acid breakdown that leads to the Krebs cycle to make glucose.
--caused by defect in methylmalonyl CoA mutase
--affects BCAA's again
--degradation to succinyl CoA doesn't happen
--propionyl CoA requires biotin
--BCAAS --/--> SUCCINYL CoA --> TCA CYCLE
--B12 = 5'-deoxyadenosylcobalamin
--some forms of the disease respond to high doses of B12
--BCAAs = Valine, isoleucine and leucine
PHENYLKETONURIA
What is the defect in classic PKU? How is it treated? What urinary metabolites are associated with PKU?
Phenylketonuria (PKU)
--an autosomal recessive genetic disorder
--deficiency in the enzyme phenylalanine hydroxylase (PAH)
--PAH metabolizes the amino acid phenylalanine to the amino acid tyrosine
--PHENYLALANINE --/--> TYROSINE
--When PAH is deficient, phenylalanine accumulates and is converted into phenylpyruvate (also known as phenylketone), which are detected in the urine.
--appears in an infant 2-4 weeks after birth
--can test for pku in urine
--incidence: hyperphenylalaninemia affects about 1:10,000-20,000 Caucasian or Oriental births
--incidence in African Americans is far less, equally frequent in males and females
--if untreated, BAD: progressive mental retardation, seizures, death.
CAN BE DIET CONTROLLED: low in phenylalanine and high in tyrosine can be a very effective treatment. There is no cure. Damage done is irreversible so early detection is crucial.
--DETECT VIA: HPLC test or the older Guthrie test
--national biochemical screening: routine Newborn Screen performed 24-28 hrs after birth
--EARLY S/Sx:
----About 50% of untreated infants have early symptoms (none of these are in all cases)
----vomiting, irritability, an eczema-like rash, and a mousy odor to the urine.
----some have increased muscle tone, and more active muscle tendon reflexes
----prominent cheek and upper jaw bones with widely spaced teeth
----poor development of tooth enamel, and decreased body growth
----eczema
----microencephaly
----albinism--may just appear blue eyed and fairer skinned than family and not be albino!
----a "musty odor" to the baby's sweat and urine (due to phenylacetate, one of the ketones produced)
----infant fails to attain early developmental milestones
----progressive impairment of cerebral function
--LATE S/SX:
----Hyperactivity
----EEG abnormalities
----seizures
----severe mental retardation later in life.
