How are ketogenic and glucogenic defined with reference to amino acids? Ketogenic aa's can be converted to acetyl CoA or acetoacetyl CoA. Glucogenic aa's produce pyruvate or Krebs cycle intermediates.

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.