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Which amino acids are important for ketogenesis?
Leucine
Lysine
Phenylalanine:
Derivatives
Phenylalanine-->
-->Tyrosine-->Thyroxine
Tyrosine-->Dopa-->Melanin
Dopa-->DA
DA-->NE
NE-->Epi
Tryptophan:
Derivatives
Tryptophan + B6-->Niacin-->NAD+/NADP+

Tryptophan + BH4-->5-HT-->Melatonin
Histidine:
Derivatives
Histidine + B6-->Histamine
Glycine:
Derivatives
Glycine + B6-->Porphyrin-->Heme
Arginine:
Derivatives
Arginine-->Creatine, Urea, Nitric Oxide
Glutamate:
Derivatives
Glutamate-->Glutathione

Glutamate + B6-->GABA via GLUTAMATE DECARBOXYLASE (REQUIRES B6)
Describe the first three steps of phenylalanine metabolism.
Phenylalanine-->Tyrosine via PHENYLALANINE HYDROXYLASE

Tyrosine-->Dopa (Dihydroxyphenylalanine) via TYROSINE HYDROXYLASE

Dopa-->Dopamine via Dopa Decarboxylase REQUIRES B6
Effect of carbidopa on phenylalanine metabolism.
Carbidopa inhibits Dopa decarboxylase (Tyroine-->Dihydroxyphenylalanine aka 'dopa')
Phenylketonuria:
Pathophys
Presentation
Labs
Treatment
Due to dec'd phenylalanine hydroxylase or dec'd tetrahydrobiopterin cofactor (remember: Phenylalanine hydroxylase--Phenylalanine +THB-->Tyrosine + DHB)

Presntation: MR, growth retardation, seizures, fair skin, eczema, musty (mousy) body odor

Phenylketones in urine (phenylacetate, phenylpyruvate, phenyllactate)

Tx: Low phenylalanine (contained in aspartame) and high tyrorsine in diet
Alkaptonuria:
Pathophys
Presentation
Deficiency of homogenetisic acid oxidase in degradative pathway of tyrosine to fumarate

Benign dz

Findings: dark connective tissue, brown pigmented sclera, arthralgias (homogentisic acid is toxic to cartilage), urine turns black if left out for a while
Albinism:
Pathophys
Congenital deficiency of:
-Tyrosinase (inability to synthesize melanin from tyrosine)--Aut Recessive

-Defective tyrosine transporters (dec'd amounts of tyrosine and thus melanin)
Describe the possible fates of homocysteine.
Homocystinuria:
Pathophys
Presentation
Treatment
3 forms:
1) Cysathionine synthase deficiency
2) Dec'd affinity of cystathionine synthase for pyridoxal phosphate
3) Homocysteine methyltransferase deficiency

Findings: In'cd homocysteine in urine, MR, osteoporosis, tall stature, kyphosis, lens subluxation (downard and inward), atherosclerosis (stroke, MI)

Tx: Dec'd methionine, inc'd cysteine in diet; supplement B12, folate, B6
Cystinuria:
Pathophys
Treatment
Hereditary defect of renal tubular amino acid transporter for cysteine, ornithine, lysine, and arginine in PCT of kidneys.

Excess cystine in urine can lead to the precipitation of cystine kidney sontes (staghorn calculi).

Tx: Acetazolamide to alkalinize urine.
Maple Syrup Urine Disease:
Pathophys
Blocked degradation of BRANCHED amino acids (I LOVE VERMONT maple syrup--Isoleucine, Leucine, Valine)

Causes severe CNS defects, MR, death
Hartnup Disease:
Pathophys
Presentation
Defective neural amino acid transporter on renal/interstitial epithelium causes tryptophan excretion in urine and dec'd absorption from gut

Leads to pellagra--diarrhea, dementia, dermatitis, death
Which genetic syndrome:
1 000-fold risk of developing skin CA
Xeroderma pigmentosa
Which genetic syndrome:
Alcoholics~ B1 defic. ~neurologic defects
Pyruvate dehydrogenase def
Which genetic syndrome:
Abnormal collagen type I synthesis
OI
Which genetic syndrome:
Absence of HGPRTase
Lesch-Nyhan Syndrome
Which genetic syndrome:
Deficiency of aldolase B
Fructose intolerance
Which genetic syndrome:
Defective excision repair ~ thymidine dimer formation
Xeroderma Pigmentosa
Which genetic syndrome:
Deficiency of cystathionine synthase
Homocysteinuria
Which genetic syndrome:
Heinz bodies
G6PD Def
Which genetic syndrome:
Musty/mousy odor, albinism, MR, eczema
PKU
Which genetic syndrome:
Galactose-1-P uridyl transferase deficiency—>MR, HSM, cataracts
Galactosemia
Which genetic syndrome:
Rx- no NutraSweet, increased dietary tyrosine
PKU
Which genetic syndrome:
Deficiency of tyrosinase
Albinism
Which genetic syndrome:
Hyperextensible skin, loose joints, bleeding tendency
Ehlers-Danlos
Which genetic syndrome:
Decreased NADPH due to lack of HMP enzyme
G6PD Def
Which genetic syndrome:
Inherited defect in tubular amino acid transporter
Cystinuria
Which genetic syndrome:
Rx- decreased dietary methionine, increased cystine + B6
Homocystinuria
Which genetic syndrome:
Deficiency in homogentisic acid oxidase
Alkaptonuria (aka ochronosis)
Which genetic syndrome:
Hypoglycemia +jaundice + cirrhosis
Fructose intolerant
Which genetic syndrome:
Self-mutilation, gout, aggression, choreoathetosis
Lesch-Nyhan syndrome
Which genetic syndrome:
Blocked degradation of branched chain amino acids
Maple Syrup Urine Dz
Which genetic syndrome:
Bloating, cramps, osmotic diarrhea
Lactose Intolerance
Which genetic syndrome:
Rx- acetazolamide to alkalinize urine
Cystinuria to prevent cysteine stones
Which genetic syndrome:
Deficiency results in a combined B and T cell deficiency
Adenosine deaminase deficiency in SCID
Which genetic syndrome:
Rx- decreased fructose and sucrose intake
Fructose intol
Which genetic syndrome:
Rx- increased intake of ketogenic nutrients (fats)
Pyruvate DH def
Which genetic syndrome:
Dark brown urine, organs, and connective tissue; benign disease
Alkaptonuria
Which genetic syndrome:
Multiple fractures + blue sclera
OI
Which genetic syndrome:
Rx- exclude galactose and lactose from diet
Galactosemia
What toxic product does amino acid catabolism generate?

Describe its removal.
AA catabolism generates nitrogen (NH4+); converted urea and excreted by kidneys:

CO2 + NH4+-->Carbamoyl Phosphate via CARBAMOYL PHOSPHATE SYNTHETASE I (RLS!!!)

TO MITOCHONDRIA!-->Citrulline (via ORNITHINE TRANSCARBAMOYLASE)-->-->-->-->Urea

TO KIDNEY!
Ornithine transcarbammoylase deficiency:
Pathophys
Presentation
Def. in the enzyme that converts Carbamoyl phosphate (product of NH4 breakdown) into Citrulline

interferes with bodys ability to eliminate ammonia

Excess carbamoyl phosphate converted to orotic acid and found in blood/urine
Dec'd BUN
Syx of hyperammonemia
Hyperammonemia:
Pathophys
Presentation
Treatment
Can be acq'd (liver dz) or hereditary (urea cycle enzyme def)

Excess NH+ depletes alpha-ketoglutarate-->inhibition of TCA

Results in tremor, slurred speech, somnolence, vomiting, cerebral edema, blurred vision

Tx: LImit protein in diet
Benzoate or phenylbutyrate (bind aa and lead to excretion)
How are fatty acids synthesized.

Begin with Acetyl-CoA.
AcetylCoa (in mitochondria)
-->Citrate Shuttle to Cell Cytoplasm

-->AcetylCoa + CO2 + Biotin**-->Malonyl-CoA-->FA (plamitate)
Describe how fatty acids are degraded.
FA + CoA-->Acyl-CoA (not ACETYL CoA) va Fatty Acid CoA Synthetase

Acyl-CoA-->Carnitine Shuttle-->Mitochondria

-->Beta-oxidation to break down acetyl-CoA groups-->Ketone bodies OR TCA cycle
Carnitine deficiency:
Effects
Inability to transport LCFAs into mitochondria, resulting in toxic accumuln

Causes weakness, hypotonia, HYPOKETOTIC, HYPOGLYCEMIA
Where is nascent HDL manufactured?

Describe its maturation and functions.
Nascent HDL produced by liver and intestine.

Interacts with LCAT (lecithin-cholesterol acyltransferase) to become Matura HDL

Mature HDL interacts with CETP (cholesterol ester transfer protein) to cholesterol bound can be dumped onto VLDL, IDL, LDL

Mature HDL then reabsorbed and sent to liver
Pancreatic lipase:
Role
Degrades dietary TG in small intestine
Lipoprotein lipase:
Role
Degrades TG circulating in chylomicrons and VLDLs
Hepatic TG lipase:
Role
Degrades TG in IDL
Hormone-sensitive lipase:
Role
Degrades TG stored in adipocytes
What are the differ apolipoproteins and what are their roles?
A-1: activates LCAT (nascent HDL-->Mature HDL)

B-100: binds to LDL receptor, mediates VLDL secretion

C-II: Cofactor for lipoprotein lipase

B-48: chylomicron secretion

E: Extra (remnant) uptake

B-48

E
LDL vs HDL:
Role
LDL is Lousy; transports cholesterol from liver to tissues

HDL is Healthy; transports cholesterol from periphery to liver
Role of chylomicrons.
Delivers dietary TGs to peripheral tissue.

Delivers cholesterol to liver in form of chylomicron remnants. Secreted by intestinal epithelial cells.
Familial hyperchylomicronemia:
Labs
Pathophys
Lipoprotein lipase deficiency (or altered apolipoprotein C-II)

Causes pancreatitis, HSM, xanthomas. No inc'd risk atherosclerosis.

Labs: Elevated TG, cholesterol (elevated chylomicrons)
Familial hypercholesterolemia:
Labs
Pathophys
Autosomal DOMINANT
Absent or low LDL receptors, HIGH LDL. Causes accelerated atherosclerosis, tendon xanthomas (Achilles).

Labs; High cholesterol
Familial hypertriglyceridemia:
Pathophys
Hepative overproduction of VLDL; causes pancreatitis
What metabolic processes occur in the mitochondria?
FA oxidation (beta-oxidation)
Acetyl-Coa production
TCA
Ox-Phos
What metabolic processes occur in the cytoplasm?
Glycolysis
FA synthesis
HMP shunt
Protein synthesis (RER)
Steroid synthesis (SER)
What metabolic processes occur in both the mitochondria AND cytoplasm?
HUGs take two:
Heme synthesis
Urea cycle
Gluconeogenesis
Rate limiting enzyme:
Heme synthesis
Aminolevulinate synthase
Rate limiting enzyme:
Bile acid synthesis
7 alpha-hydroxylase
What are the essential amino acids?
PVT TIM HALL

Phe
Val
Thr
Trp
Isoleu
Met
His
Arg
Leu
Lys
What is the mechanism of action of lactulose?
Sugary syrup broken down in gut to create acidic environment to create ammonia to ammonium anion; traps it and pulls other ammonium to gut for excretion
Which amino acid is a precursor to:
Histamine
Histidine
Which amino acid is a precursor to:
Porphyrin, heme
Glycine
Which amino acid is a precursor to:
NO
Arginine
Which amino acid is a precursor to:
GABA
Glutamate
Which amino acid is a precursor to:
S-adenosyl-methionine
Methioning
Which amino acid is a precursor to:
Creatine
Arginine
Compare carbamoyl phosphate I to carbamoyl phosphate II.
CPS I:
Urea cycle
Found in mitochondria
Gets nitrogen from ammonium

CPS II:
Pyrimidine synthesis
Found in cytosol
Gets nitrogen from glutamine
Rate-limiting enzyme:
Urea cycle
Carbamoyl Synthetase I
Rate-limiting enzyme:
Hexose monophosphate pathway
G6PD
Rate-limiting enzyme:
Fatty acid synthesis
AcetylCoA Carboxylase
Rate-limiting enzyme:
beta-oxidation of fatty acids
Carnitine acyltransferase
Rate-limiting enzyme:
Ketone body synthesis
Hmg CoA Synthase
Rate-limiting enzyme:
Cholesterol synthesis
Hmg CoA reductase
Rate-limiting enzyme:
Bile acid synthesis
7-alpha-hydroxylase
Rate-limiting-enzyme:
Heme synthesis
Aminolevulinate synthase
What deficiency causes familial hypercholesterolemia?
Def in LDL receptors
A patient with PKU should have diet low in phenylalanine.

What other dietary modifications should a patient with PKU make?
Inc'd tyrosine in diet
Replacing THB cofactor
A full-term neonate becomes mentally retarded and hyperactive and has a musty odor.
What is the diagnosis?
PKU
A 2-year-old girl has an increase in abdominal girth, failure to thrive, and skin/hair depigmentation.

What is her diagnosis?
Kwashiorkor
A middle-aged man has dark spots on his sclera and has noted that his urine turns black when left sitting for a period of time.

What is the diagnosis?
Alkaptonuria
A patient has a genetic disease in which the treatment includes protein restriction to prevent mental retardation, ketoacidosis, and death.

What is the diagnosis?
Maple Syrup Urine Dz
An 18-year-old female has moderate generalized abdominal pain, normal WBC, and no fever. She has
paresthesias in her lower extremities.

What is her diagnosis?
Acute intermittent porphyria
A 45-year-old male alcoholic gets blistering lesions in sun-exposed areas especially the dorsum of the hands. He also has hypertrichosis of the face.

What is the diagnosis?
Porphyria Cutanea Tarda
What is the treatment for homocystinuria?
Tx:
Dec methionine
Inc cystine
Inc B6, ,B12, folate
Cyclosporine:
Drug Class
MOA
AE
immunosuppressant

Blocks differentiation/activation of T cells by inhibiting IL-2 production

Nephrotoxic unless given mannitol diuresis
Tacrolimus:
Drug Class
MOA
AE
Immunosuppressant; inhibits secretion of IL-2 (no T cell diff/activation)

AE: significant! nephrotox, peripheral neuropathy, HTN, pleural effusion, hyperglycemia
Sirolimus:
Drug Class
MOA
Immunosuppressant

Binds to mTOR, inhibits T-cell prolifern in response to IL-2
Which immunosuppressant:
Precursor of 6-mercaptopurine
Azathioprine
Which immunosuppressant:
May prevent nephrotoxicity with mannitol diuresis
Cyclosporine
Which immunosuppressant:
Antibody that binds to CD3 on T cells
Murominab
Which immunosuppressant:
Antibody that binds IL-2 receptor on activated T cells
Daclizumab
Which immunosuppressant:
Inhibits calcineurin –> loss of IL-2 production –> blockage ofT cell differentiation and activation
Cyclosporine
Which immunosuppressant:
Binds FK-binding protein –> loss of IL-2 production
Tacrolimus
Which immunosuppressant:
Binds FKBP-12 –> inhibition of mTOR –>inhibition ofT cell proliferation
Sirolimus
Which immunosuppressant:
Metabolized by xanthine oxidase, therefore allopurinol increases its toxicity
Azathioprine