Anatomy to Immunology Flashcards
Infant with growth retardation, hepatomegaly, hypoglycemia, ketoacidosis – liver biopsy shows hepatic fibrosis without fat accumulation and accumulation of small chain dextrin-like material in hepatocyte cytosol?
Cori disease
glycogen storage disease Type III
absence of debranching enzyme (alpha-1,6-glucosidase)
What is vitamin B5? What is it used in?
Pantothenic acid
essential component of coenzyme A (CoA, cofactor for acetyl transfers) and fatty acid synthase
TCA cycle steps: OAA to citrate with acetyl-CoA, succinyl Co-A intermediate
What is Type I glycogen storage disease? What is Type III? How to tell the difference?
Von Gierke disease (Type I)
glucose-6-phosphatase deficiency (normally functions to get glucose out of liver into blood)
Cori disease (Type III) debranching enzyme deficiency (normally takes last glucose off branch)
Type III is a milder form of type I with normal blood lactate levels;
Type III has NO fatty infiltration of the liver and short dextrin-like structures can be seen in the cytosol;
Type I has hepatic steatosis as a cardinal feature
What are triglycerides broken down into? What is the fate of these products and where does this take place?
Triglycerides broken down by hormone-sensitive lipase into:
glycerol and fatty acids
Fatty acids are transported via the carnitine shuttle to the mitochondrial matrix where the acyl-CoAs are broken down into acetyl-CoA to be fed into the TCA cycle or used as ketone bodies.
Glycerol is transported to the liver (ONLY) and converted by glycerol kinase into glycerol 3P (used in glycolysis or gluconeogenesis).
What is the role of aldose reductase?
1) Trapping of glucose in the cell by converting it to its alcohol counterpart, sorbitol.
Aldose reductase takes glucose -> sorbitol
(Sorbitol dehydrogenase takes sorbitol -> fructose in the liver, ovaries, and seminal vesicles to create fructose; low levels in the lens and absence in the retina, kidneys, and Schwann cells leads to sorbitol accumulation and damage in diabetes)
2) Converts galactose to galactitol (leads to toxic accumulation in lens of eye) in disorders of galactose metabolism (galactokinase deficiency and classic galactosemia/galastose1P-uridyltransferase deficiency)
Both products of aldose reductase, if allowed to accumulate, causes cataracts!!
What is the first steps of pyruvate conversion in gluconeogenesis? Requirements and activators?
1) Pyruvate carboxylase: pyruvate –> OAA (in mitochondria)
- Requires biotin and uses 1ATP
- Activated by acetyl-CoA (build-up in TCA cycle leads to activation of gluconeogenesis rxn)
[Malate shuttle out of mitochondria and into cytosol]
2) Phosphoenolpyruvate carboxykinase: OAA –> PEP (in cytosol)
- Requires GTP
What is N-myc, c-Jun, and c-Fos? What is S-100?
transcription factors that bind DNA
S-100 is a marker for neural crest derivation (melanocytes, Schwann cells), as well as dendritic cells (Langerhans cells, etc.)
8yo fasting 1day with vomiting, lethargy, mildly enlarged liver, hypoglycemia, and low plasma ketone level?
hypoglycemia after prolonged fasting with inappropriately low levels of ketone bodies suggests impaired beta-oxidation!!
Impaired beta-oxidation most commonly results from defects in the first enzyme in the pathway: acyl-CoA dehydrogenase (converts acyl-CoA into acetyl-CoA in the mitochondria)
(could also be a carnitine deficiency – carnitine used to shuttle acyl-CoA into the mitochondria to be converted to acetyl-CoA)
Hypoketotic hypoglycemia?
Disorders of fatty metabolism:
- Carnitine deficiency
inability to transport long-chain fatty acids (Acyl-CoA) into the mitochondria, leading to toxic accumulation - Acyl-CoA dehydrogenase deficiency
inability to break acyl-CoA into acetyl-CoAs
(since acetyl-CoA is a positive allosteric regulator of pyruvate carboxylase in gluconeogenesis, the absence decreases fasting glucose levels)
Disorders of fatty acid metabolism?
present with hypoketotic hypoglycemia
- carnitine deficiency
- acyl-CoA dehydrogenase deficiency
restrict ketone body (acetoacetate, beta-hydroxybutyrate, acetone) production
What cells cannot utilize ketone bodies?
cells lacking mitochondria (RBCs)
hepatocytes (lack the enzyme to convert acetoacetate to acetyl-CoA)
Where does the pentose phosphate pathway take place? Beta-oxidation of fatty acids? Ketogenesis? Pyruvate carboxylation?
Cytoplasm
Beta-oxidation, ketogenesis, pyruvate carboxylation = all take place in the mitochondria
Hypoglycemia with high intracellular NADH level?
indicates a fuel other than glucose is being metabolized
hepatic ethanol catabolism produces NADH and inhibits gluconeogenesis:
- high intracellular ratio of NADH favors conversion of pyruvate to lactate, and OAA to malate
- pyruvate and OAA are intermediates in gluconeogenesis, so conversion inhibits gluconeogenesis
What branch of the pentose phosphate pathway involves transketolases and what is required for transketolase action?
Nonoxidative/reversible
30yo man ingested broad beans and now shows fatigue, dark urine, back pain, jaundice and pallor.
G6PD deficiency
exposure to fava beans causes acute hemolytic anemia
Describe the products of the oxidative branch of the pentose phosphate pathway. What are they used for? Rate-limiting step?
NADPH
ribulose-5P
CO2
NADPH used for anabolic reactions (cholesterol and fatty acid synthesis) and is the only method for reducing glutathione (for repair of oxidative damage) in RBCs.
Ribulose-5P can be further shunted into the nonoxidative/reversible branche of the pentose phosphate pathway.
Glucose-6P dehydrogenase = rate limiting step
Describe the nonoxidative branch of the pentose phosphate pathway.
uses transketolases and transaldolases with a vitamin B1/thiamine requirement
products are Ribulose 5P and intermediates of glycolysis
What reactions is lipoic acid a cofactor in? What inhibits lipoic acid and what are the findings?
Pyruvate dehydrogenase (PDH deficiency = increased lactate and alanine) Branched-chain ketoacid dehydrogenase (Maple syrup urine disease = increased alpha-keotacids in blood)
Arsenic inhibits lipoic acid.
Findings: vomiting, rice-water stools, garlic breath
What are the four fates of pyruvate and what are the enzymes that catalyze each pathway?
Conversion to:
1) Alanine by alanine aminotransferase (ALT)
2) OAA by pyruvate carboxylase (biotin-dependent)
3) Acetyl-CoA by pyruvate dehydrogenase (lipoic acid, thiamine/B1)
4) Lactate by lactate dehydrogenase
What is maple syrup urine disease? Inheritance? Findings? Treatment?
decreased alpha-ketoacid dehydrogenase (B1 dependent)
autosomal recessive
blocked degradation of branched amino acids (Isoleucine, Leucine, Valine)
Findings: CNS defect, intellectual disability, death
Treatment: restriction of branched AAs in diet, thiamine/B1 supplementation
What is vitamin B1? Involved in what reactions? Deficiency seen in?? Presentation?
Thiamine (thiamine pyrophosphate/TPP)
TPP cofactor in:
- PDH
- alpha-ketoglutarate dehydrogenase (alpha-KG to succinylCoA)
- transketolase
- branched-chain ketoacid dehydrogenase (maple syrup urine disease)
Deficiency due to malnutrition and alcoholism.
Presentation
- Wernicke-Korsakoff syndrome
- Beriberi (dry = polyneuritis, muscle wasting; wet = high-output CHF/dilated cardiomyopathy, edema)
Deficiency of vitamin B1 leads to?
impaired glucose breakdown = ATP depletion that can worsen with glucose infusion
3mo with muscle hypotonia, feeding difficulties, hepatomegaly, cardiomegaly. Muscle biopsy shows polysaccharide accumulation within lysosomes. Inheritance?
Glycogen storage disease Type II (Pompe disease)
POMPE TRASHES THE PUMP – heart, liver, muscle
deficiency in lysosomal alpha-1,4-glucosidase (acid maltase)
What is aldolase B deficiency? What cannot be consumed?
cannot metabolize fructose to glyceraldehyde and DHAP (life-threatening due to phosphate depletion which inhibits glycolysis and gluconeogenesis)
Cannot consume fructose or sucrose (glucose and fructose)
