Metabolism Flashcards
Mitochondria
Fatty acid oxidation, acetyl CoA production, TCA cycle, oxidative phosphorylation
Cytoplasm
Glycolysis, fatty acid synthesis, HMP (ribose) shunt, protein synthesis (RER), steroid synthesis (SER), cholesterol synthesis
Mitochondria and Cytoplasm metabolism
Heme synthesis, urea cycle, gluconeogenesis (HUG takes two)
Kinase
Uses ATP to add high energy phosphate group onto substrate, ex phosphofructokinase
Phosphorylase
Add inorganic phosphate group onto substrate without energy, ex glycogen phosphorylase
Phosphatase
Removes phosphate group from substrate, ex fructose-1.6-biphosphatase
Dehydrogenase
Catalyzes oxidation-reduction reactions, ex pyruvate dehydrogenase
Carboxylase
Transfers CO2 group with the help of biotin, ex pyruvate carboxylase
Hydroxylase
Adds -OH gruop onto substrate, ex tyrosin hydroxylase
Mutase
Relocates a functional group within a molecule
Glycolysis
RLE: phosphofructokinase
Up: AMP, fructose-2,6-biphosphate
Down: ATP, citrate
Gluconeogenesis
RLE: fructose-1,6-biphosphatase
Up: ATP, acetyl CoA
Down: AMP, fructose-2,6-biphospate
TCA cycle
RLE: isocitrate dehydrogenase
Up: ADP
Down: ATP, NADH
Glycogenesis
RLE: glycogen synthase
Up: glucose-6-phosphate, insulin, cortisol
Down: epinephrine, glucagon
Glycogenlysis
RLE: glycogen phosphrylase
Up: epinephrine, glucagon, AMP
Down: G6P, insulin, ATP
HMP (pentose) shunt
RLE: Glucose-6-phosphate-dehydrogenase
Up: NADP
Down: NADPH
Urea cycle
RLE: carbamoyl phosphate synthetase I
Up: n-acetylglutamate
Fatty acid synthesis
RLE: acytel CoA carboxylase
Up: insulin, citrate
Down: glucagon, palmitoyl-CoA
Fatty acid oxidation
RLE: carnitine acyltransferase I
Up: malonyl-CoA I
Ketogenesis
RLE: HMG-CoA synthase
Cholesterol synthesis
RLE: HMG CoA reductase
Up: insule, thyroxine
Down: glucagon, cholesterol
ATP production
Anaerobic glycolysis produces 2 net ATP
Aerobic metabolism of glucose produces 32 net APT (30 via TCA and ETC and 2 from anaerobic glycolysis)
NAD (nicotinamides)/FAD
Used in catabolic processes to carry reducing equivalents away as NADH/FADH
NADP/NADPH
Used in HMP shunt for anabolic process (steroid and fatty acid synthesis as supply of reducing equivalents), respiratory burst (immune defense), cytochrome 450 system (reducing agent), and glutathion reductase
Hexokinase
Phosphorylate glucose to G6P for glycolysis
Located in most tissues but not liver or beta cells in pancreas
NOT induced by insulin
Feedback inhibited by G6P concentration
Gene mutation NOT associated with diabetes
At low glucose concentration, sequester glucose in tissue
Glucokinase
Phosphorylate glucose to G6P
Located in liver and beta cells of pancreas
Induced by insulin
NOT feedback inhibited by G6P
Gene mutation associated with diabetes
At high glucose concentration, glucose stored in liver
F2,6BP regulation
FBPase 2 and PFK-2 are the same bifunctional enzyme whose function is reversed by phosphorylation by protein kinase A
Fasting state:
Increased glucagon –> increased cAMP –> increased protein kinase A –> increased FBPase 2 and decreased PFK-2, less glycolysis and more gluconeogenesis
Fed state:
Increased insulin –> decreased cAMP –> decreased protein kinase –> decreased FBPase 2 and increased PFK-2, more glycolysis and less gluconeogenesis
Pyruvate dehydrogenase complex
Mitochondrial enzyme complex linking glycolysis and TCA cycle, differentially regulated in fed/fasting state (active in fed state)
Reaction: pyruvate (from glycolysis) + NAD + CoA –> acetyl-CoA + CO2 + NADH
The complex contains 3 enzymes that requires 5 cofactors: pryophosphate, FAD, NAD, CoA, lipoic acid
Deficiency: build up of pyruvate that gets shunted to lactate and alanine leading to neurologic defects, lactic acidosis. Treatment w/ increased intake of keogenic nutrients
Pyruvate metabolism
- Alanine aminotransferase (ALT) via B6: converts pyrvate to alanine, alanine carries amino groups to the liver from muscle for urea cycle
- Pyruvate carboxylase via B7 biotin: converts pyruvate to oxaloacetate (in mitochondria), which can replenish TCA cycle or be used for gluconeogensis
- Pyruvate dehydrogenase via B1, B2, B3, B5, lipoic acid: converts pyruvate to acetyl-CoA for TCA cycle
- Lactic acid dehydrogenase via B3: end of anaerobic glycolysis (major pathway in RBC, leukocytes, lens, cornea, testes)
TCA cycle Detail
Conversion of pyruvate to acetyl-CoA produces 1 NADH
TCA produces 3 NADH, 1 FADH2, 1 GTP per acetyl-CoA, which converts to 10 ATP (NADH = 2.5 ATP, FADH2 = 1.5 ATP)
Citrate Is Kreb’s Starting Substrate For Making Oxaloacetate
Electron transport inhibitors
Directly inhibit electron transport, causing a decrease in proton gradient and block of ATP synthesis
Ex: Rotenone (insecticide), cyanide, antimycin A (produced by Streptomyces, carbon monoxide
ATP synthase inhibitors
Directly inhibit mitochondrial ATP synthase
Ex: oligomycin (produced by Streptomyces)
Uncoupling agents
Increase permeability of membrane, causing a decrease in proton gradient and increased O2 consumption. ATP synthesis stops but electron transport continues.
Produces heat
Ex: 2-4 dinitrophenol (weight loss), aspirin
HMP shunt pentose phosphate pathway reactions
Provides a source of NADPH from ABUNDANTLY available G6P
NADPH is required fro reductive reactions such as glutathion reduction inside RBC to reduce oxidative stress and fatty acid and cholesterol synthesis
Also used for ribose synthesis
Oxidative reaction: G6P –> ribulose-5-Pi + 2 NADPH + CO2 with G6PD as RLE
Nonoxidate reaction: ribulosse-5-Pi –> ribose-5-Pi + G3P + F6P with phosphopentose iosmerase transketolases, needing B1 (thiamine)
Respiratory burst (oxidative burst)
Involves activation of phagocyte NADPH oxidase complex (in neutrophils, monocytes), which utilizes O2 as a substrate to release reactive oxygen species as immune response
G6PD deficiency
X-linked recessive disorder, more prevalent among blacks
Decreased NADPH in RBC leads to hemolytic anemia
Heinz bodies: oxidized hemoglobin precipitated within RBC
Bite cells: result from phagocytic removal of Heinz bodies by splenic macrophages
Essential fructosuria
Defect in fructokinase, autosomal recessive
Benign with fructose appears in blood and urine
Fructose intolerance
Autosomal recessive
Hereditary deficiency of aldolase B, leading to accumulation of fructose-1-P, a decrease in available phosphate, and inhibition of glycogenolysis and gluconeogenesis
Symptoms: hypoglycemia, jaundice, cirrhosis, vomiting
Treatment: decrease intake of both fructose and sucrose
Galactokinase deficiency
Autosomal recessive
Galactitol accumulates, leading to galatose in blood and urine and infantile cataracts
Galactosemia
Autosomal recessive
Absence of galactose-1-phosphate uridyltransferase, leading to damage caused by accumulation of galacitol, failure to thrive, jaundice, hepatomegaly, infantile cataracts, and intellectual disability
Treatment: exclude galactose and lactose from diet
Lactase deficiency
Primary: age-dependent decline after childhood
Secondary: loss of brush border due to gastroenteritis, autoimmune disease
Congenital: rare
Symptoms: bloating, cramps, flatulence, osmotic diarrhea
Treatment: avoid dairy, choose lactose-free milk
Essential amino acids
Methionine, valine, histidine, isoluecine, phenylalanine, threonine, tryptophan, leucine, lysine
Any Help In Learning These Little Molecules Proves Truly Valuable
Urea cycle Detail
Amino acid catabolism results in the formation of metabolites (pyruvates, acetyl CoA) together with excess NH3
NH3 in liver is converted in liver mitochondria to carbamoyl phosphate via carbamoyl phosphate synthetase I (N-acetylgutamate as cofactor) and evntually to urea via urea cycle and excreted by kidney
Ordinarily (orithine) Careless (carbamoyl phosphate) Crappers (citruline) Are Also Frivolous About Urination
Hyperammonemia
Can be acquired (eg liver disease) or hereditary (urea cycle enzyme deficiencies)
Results in excess NH4+, which depletes alpha-keotglutarate and leads to inhibition of TCA cyle
Signs: tremor (asterixis), slurring of speech, somnolence, vomiting, cerebral edema, blurring of vision
Treatment: limit protein diet, lactulose to acidify the GI tract and trap NH4+ for GI excretion
N-acetylglutamate deficiency
Hyperammonemia
Presentation is identical to carbamoyl phosphate synthetase I deficiency
Increased orithine concentration with NORMAL urea cycle enzymes suggest N-acetylglutamate deficiency
Orthinie transcarbamylase deficiency
X-linked recessive
Enzyme converts carbamoyl phosphate and ornithine to citrulline as part of urea cycle
Findings: increased orotic acid in blood and urine, decreased BUN, symptoms of hyperammonemia
Phenylketonuria
Autosomal recessive
Due to decreased phenyalanine hydroxylase. Tyrosine becomes essential AA
Findings: increased phenalaine, intellectual disability, growth retardation, seizures, fair skin, eczema, musty body odor
Treatment: decreased phenylalanine and increased tyrosine in diet
Alkaptonuria
Autosomal recessive, benign
Congential deficiency of homogentisate oxidase in the degradative pathway of tyrosine
Findings: dark connective tissue, brown pigmented sclerae, debilitating arthralgias (toxicity to cartilage)
Homocystinuria
Autosomal recessive
Methionine cystathionine –> cysteine
Findings: increased homocysteine in urine, intellectual disability, osteoporosis, thrombosis, atherosclerosis
Treatment: depending on which enzyme is deficient
Cystinuria
Autosomal recessive 1:7000
Hereditary defect of renal proximal tubule and intestinal AA transporter for Cysteine
Excessive cysteine in the urine can lead to precipitation of hexagonal cystine stones
Treatment: urinary alkalinization and good hydration
Maple syrup urine disease
Autosomal recessive
Blocked degradation of branched amino acids (isoleucine, leucine, valine) due to decreased alpha ketoacid dehydrogenase
Findings: urine smells like maple syrup, CNS defects, death
Treatment: restriction of branched AA, thiamine supplement
Skeletal muscle glycogen
Glycogenolysis –> G1P –> G6P, which is rapidly metabolized during exercise
Hepatocytes glycogen
Stored and undergoes glycogenolysis to maintain blood sugars at appropriate levels
Glycogen branches have alpha 1-6 bonds while linkages have alpha 1-4 bonds
Von Gierke disease
Glycogen storage disease, Autosomal recessive
Glucose 6 phosphatse deficiency
Severe fasting hypoglycemia, increased glycogen in liver, hepatomegaly
Treatment: frequent oral glucose
Pompe disease
Glycogen storage disease, autosomal recessive
Lysomal alpha 1-4 glucosidase deficiency
Cardiomyopathy
Pompe trashes the Pump
Cori disease
Glycogen storage disease, autosomal recessive
Debranching enzyme deficiency
Milder form of Von Gierke
McArdle disease
Glycogen storage disease, autosomal recessive
Skeletal muscle glycogen phosphorylase deficiency
Increased glycogen in muscle that cannot be broken down, leading to painful muslce cramps and myoglobinuria with strenuous exercise. Arrhythmia w/ electrolyte abnormalities
McArdle Muscle
Fabry disease
Lysosomal storage disease, XR
Alpha galactosidase A deficiency
Peripheral neuropahty, cardivascular/renal disease
Gacher disease
Lysosomal storage disease, AR
Glucocerobrosidase deficiency
Hepatosplenomegaly, pancytopenia, aspectic necrosis of bone, Gaucher cells (lipid laden macrophages resembling crumbling tissue paper)
Niemann-Pick disease
Lysosomal storage disease, AR
Sphingomyelinase deficiency
Progress neurodegeneration, hepatosplenomegaly, cherry red spots on macula, foam cells (lipid laden macrophages)
Tay-Sachs disease
Lysosomal storage disease, AR
Hexosaminidase A deficiency
Progressive neurodegeneration, developmentally delayed, cherry red spots on macula, NO hepatomegaly
Krabbe diseaes
Lysosomal storage disease, AR
Galactocerobrosidase deficiency
Peripheral neuropathy, developmental delays, optic atrophy
Metachromatic leukodystrophy
Lysosomal storage disease, AR
Arysulfatase A deficiency
Central and peripheral demyelination with ataxia and demntia
Hurler syndrome
Lysosomal storage disease, AR
Alpha-L-iduronidase deficiency
Developmental delays, airway obstruction, corneal clouding
Hunter syndrome
Lysosomal storage disease, AR
Iduronate sulfatase deficiency
Mild Hurler + aggressive behaviors, no corneal clouding
Carnitine deficiency
Inability to transport LCFAs into mitochondria for degradation, resulting in toxic accumulation
Causing weakkness, hypotonia, and hypoketotic hypoglycemia
Metabolic fuel use: fed state (after meal)
Glycolysis and aerobic respiration
Insulin stimulates storage of lipids, proteins, and glycogen
Metabolic fuel use: fasting (between meals)
Hepatic glycogenlysis (major), hepatic gluconeogensis, adipose release of FFA (minor)
Glucagon, adrenaline stimulate use of the reserve fuel
Metabolic fuel use: starvation 1-3 days
Blood glucose level maintained by hepatic glycogenolysis, adipose release of FFA, muscle and liver usage of FFA instead of glucose, hepatic gluconeogenesis from peripheral tissue lactate and alanine and glycerol from adipose tissue
Glycogen reserves depleted after day 1, glucose reserved for RBCs since RBCs lack mitochondria and cannot use FFA/ketones
Metabolic fuel state: starvation after day 3
Adipose stores (ketone becomes main source of energy)
Vitals proteins degradation accelerates w/ depletion of adipose storage
Excess storage determines survival time
Cholesterol synthesis detail
Rate limiting step is catalyzed by HMG-CoA reductase, which converts HMG-CoA to mevalonate
2/3 of plasma cholesterol is esterified by lecithin-cholesterol acyltransferase (LCAT) for VLDL, LDL, HDL transport
Stains competitively and reversibly inhibit HMG-CoA reductase
Pancreatic lipase
Degradation of dietary triglycerides in small intestine
Lipoprotein lipase
Degradation of TG circulating in chylomicrons and VLDLs Found on vascular endothelial surfaces
Hepatic TG lipase
Degradation of TG remaining in IDL
Hormone sensitive lipase
Degradation of TG stored in adipocytes
Lectinin-cholesterol acyltransferase (LCAT)
Catalyzes esterificatino of cholesterol
Cholesterol ester transfer protein (CETP)
Mediates transfer of cholesterol esters to other lipoprotein particles (VLDL, LDL, IDL)
Apoplipoprotein
E: mediates remnant uptake
A1: activates LCAT
C2: lipoprotein lipase cofactor
B48: mediates chylomicron secretion
B100: binds LDL receptor
Low density lipoprotein
Transports cholesterol from liver to tissues
Formed by hepatic lipase modification of IDL in the peripheral tissue
Taken up by target cells via receptor mediated endocytosis
High density lipoprotein
Transports cholesterol from peripheral to liver
Secreted from both liver and intestine
VLDL
Delivers hepatic TG to peripheral tissue, secreted by liver
IDL
Formed in degradation of VLDL
Delivers TGs and cholesterol to liver
Chylomicron
Delivers dietary TGs to peripheral tissue
Delivers cholesterol to liver in the form of chylomicron remnant, which are mostly depleted of their TGs
Secreted by intestinal epithelial cells
Familial dyslipidemia type 1: hyperchylomicronemia
AR, lipoprotein lipase deficiency
Increased chylomicrons and cholesterol
Causes pancreatitis, hepatosplenomegaly, pruritic xanthomas
Familial dyslipidemia type 2a: familial hypercholesterolemia
AD, absent or defective LDL receptors
Increased LDL and cholesterol
Causes accelerated atherosclerosis, tendon xanthomas, (achilles), corneal arcus
Familial dyslipdemia type 4: hypertriglyceridemia
AD, hepatic overproduction of VLDL
Increased VLDL, TG
Causes pancreatitis
