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Flashcards in Biochemistry: Metabolism Deck (141):
1

Site of metabolism:

Mitochondria

  • Fatty acid oxidation (B-oxidation)
  • Acetyl CoA production
  • TCA cycle
  • oxidative phosphorylation

2

Site of metabolism:

Cytoplasm

  • Glycolysis
  • gatty acid synthesis
  • HMP shunt
  • protein synthesis (RER)
  • steroid synthesis (SER)
  • Cholesterol Synthesis

3

Site of metabolism

Mitochondria & Cytoplasm

  • Heme synthesis
  • Urea cycle
  • Gluconeogenesis

4

Kinase

Uses ATP to add phosphate group onto substrate

5

phosphorylase

Adds inorganic phosphate onto substrate without ATP

6

Phosphatase

removes phosphate group from substrate

7

Dehydrogenase

catalyzes oxidation- reduction reactions

8

Hydroxylase

adds hydroxyl group (OH) onto substrate

9

Carboxylase

Transfers CO2 groups with help of biotin

10

Mutase

relocates a functional group within a molecule

(Methylmalonyl CoA mutase)

11

Rate Determining Enzyme:

Glycolysis

Phosphofructokinase 1 (PFK-1)

  • +
    • AMP
    • Fru 2,6 bisphosphate
    • ATP
    • Citrate

12

Rate Determining Enzyme:

Gluconeogenesis

Fructose 1,6, Bisphosphatase

  • +
    • ATP
    • Acetyl CoA
  • -
    • AMP
    • Fru 2,6 bisphosphate

13

Rate Determining Enzyme:

TCA

Isocitrate dehydrogenase

  • +
    • ADP
  • -
    • ATP
    • NADH

14

Rate Determining Enzyme:

Glycogenesis

Glycogen Synthase

  • +
    • Glucose 6 phosphate
    • insulin
    • Cortisol
  • -
    • Epinephrine
    • Glucagon

15

Rate Determining Enzyme:

Glycogenolysis

Glycogen Phosphorylase

  • +
    • Epinephrine
    • glucagon
    • AMP
  • -
    • G6P
    • insulin
    • ATP

16

Rate Determining Enzyme:

HMP shunt

Glucose 6 phosphate dehydrogenase (G6PD)

  • + NADP+
  • - NADPH

17

Rate Determining Enzyme:

De novo pyrimidine Synthesis

Carbamoyl phosphate synthetase II

 

18

Rate Determining Enzyme:

De novo purine synthesis

Glutamine phosphoribosylpyrophosphate (PRPP) amindotransferase

    • AMP
    • inosine monophosphate (IMP)
    • GMP

19

Rate Determining Enzyme:

Urea Cycle

Carbamoyl Phosphate synthetase I

  • + N-acetylglutamate

20

Rate Determining Enzyme:

Fatty acid synthesis

Acetyl CoA Carboxylase (ACC)

  • +
    • insulin
    • citrate
  • -
    • Glucagon
    • palmitoyl-CoA

21

Rate Determining Enzyme:

Fatty Acid oxidation

Carnitine acyltransferase I

  • - malonyl coA

22

Rate Determining Enzyme:

Ketogenesis

HMG-CoA Synthase

23

Rate Determining Enzyme:

Cholesterol Synthesis

HMG-CoA reductase

    • insulin
    • thyroxine
  • -
    • Glucagon
    • cholesterol

24

ATP production

  • Aerobic metabolism of glucose
    • 32 net ATP via Malate-aspartate shuttle
    • 30 net ATP via glycerol 3 phosphate shuttle
  • Anaerobic glycolysis produces only 2 net ATP per glucose molecule
  • ATP hydrolysisi can be coupled to energetically unfavorable reactions
  • Arsenic causes glycolysis to produce net 0 ATP

25

Activated carrier:

ATP

Phosphoryl groups

26

Activated carrier:

NADH, HADPH, FADH2

electrons

27

Activated carrier:

CoA, lipoamide

Acyl groups

28

Activated carrier:

Biotin

Co2

29

Activated carrier:

Tetrahydrofolate

1 carbon unit

30

Activated carrier:

SAM

CH3 groups

31

Activated carrier:

TPP

Aldehydes

32

Universal electron acceptors

Nicotinamides (NAD+ and NADP+) and flavin (FAD+)

  • NAD is generally used in catabolic processes to carry reduing equivalencts away as NADH
  • NADPH is used to anabolic processes ( steroid and fatty acid synthesis) as a supply of reducing equivalents
    • product of HMP shunt
    • repiratory burst
    • Cytochrome P450 system
    • Glutathione reductase

33

Hexokinase:

  • Tissues
  • Km
  • Vmax
  • induced by insulin?
  • Feedback inhibition?
  • Gene mutation in MODY?

catalyzes phosphorylation of glucose to yield G6P is the 1st step of glycolysis in most tissue

  • not liver or B- cells in pancreas
  • Lower Km ( increase affinity)
  • Vmax lower (decrease capacity)
  • Not induced by insulin
  • Feedback inhibited by G6P
  • No gene mutation associated with maturity onset diabetes

34

Glucokinase:

  • Tissues
  • Km
  • Vmax
  • induced by insulin?
  • Feedback inhibition?
  • Gene mutation in MODY?

Phosphorylation of glucose to G6P ( glycolysis)

  • Liver, B-cells in pancreas
  • Km: higher (lower affinity)
  • Vm: higher ( increase capacity)
  • Induced by insulin
  • no feedback inhibition by G6P
  • associated with gene mutation in maturity-onset diabetes of the young

35

Glycolysis:

Net equation

Cytoplasm

  • Glucose + 2Pi +2ADP + NAD+ -->
  • 2 pyruvate + 2ATP + 2 NADH +2H2O + 2H+

36

Glycolysis:

Reactions that require ATP

  • Glucose--> Glucose 6 phosphate
    • Hexokinase/ glucokinase
    • Glu 6P (-) hexokinase
    • Fru 6P (-) glucokinase
  • Fructose 6P--> Fru 1, 6BP
    • Phosphofructokinase 1 ( rate limiting)
    • ATP (-)
    • AMP (+)
    • citrate (-)
    • Fru 2,6 BP (+)

37

Glycolysis:

Reactions that produce ATP

  • 1,3 BPG 3 PG
    • Phosphoglycerate kinase
  • Phosphoenolpyruvate --> pyruvate
    • pyruvate kinase
    • ATP (-)
    • alanine (-)
    • Fru 1,6 BP (+)

 

38

Regulation by Fru 2,BP:

  • Fasting
  • Fed

  • Fructose 6 Phosphate Fru 2,6 BP
    • Fed: Phosphofructokinase 2
    • Fasting: Fructose bisphosphatase-2
  • Fru 6P --> Fru 1,6BP
    • PFK-1
    • (+) PFK2
    • glycolysis
  • Fru 1,6BP --> Fru 6P
    • FBPase-1
    • Gluconeogenesis
  • Fasting state
    • increased glucagon--> incr.cAMP --> incr. PKA --> Incr. FBPase-2 --> decr. PFK-2
    • Less glycolysis and more gluconeogenesis
  • Fed state
    • Incr. insulin --> decr. cAMP --> decr. PKA --> decr. FBPase-2 --> incr. PFK-2
    • more glycolysis
    • less gluconeogenesis

39

Pyruvate dehydrogenase complex

  • Reaction
  • Co-factors
  • activation 

  • Pyruvate + NAD+ + CoA --> acetyl coA + CO2 +NADH
  • Co-factors
    • pyrophosphate (B1, thiamine, TPP)
    • FAD (B2, Riboflavin)
    • NAD (B3, Niacin)
    • CoA (B5, pantothenate)
    • Lipoic acid (inhibited by arsenic)
  • Activated by exercise
    • Increases NAD+/NADH ratio
    • increase ADP
    • Increase Ca2+

40

Pyruvate dehydrogenase deficiency

Cuases a buildup of pyruvate that gets shunted to lactate (via LDH) and alanine (via ALT)

  • Neurologic defects
  • lactic acidosis
  • increase serum alanine starting in infancy
  • Tx: increase intake of ketogenic nutrients 
    • high fat or increase lysine, leucine

41

Pyruvate metabolism

  • Metabolic pathways
  • co-factors

  • Alanine
    • alanine aminot transferase
    • B6
    • carries amino groups from liver to muscle
  • Oxaloacetate
    • Pyruvate carboxylase
    • biotine
    • replenish TCA cycle or used in gluconeogenesis
  • Acetyl CoA
    • Pyruvate dehydrogenase
    • B1, B2, B3, B5, lipoic acid
    • glycolysis to TCA cycle
  • Lactate
    • lactic acid dehydrogenase
    • B3
    • anaerobic glycolysis

42

TCA Cycle

  • Produces: 3 NADH, 1 FADH2, 2CO2, 1 GTP per acetyl CoA
  • 10 ATP per acetyle CoA
  • occurs in the mitochondria
  • a-ketoglutarate dehydrogenase requires
    • B1, B2, B3, B5, lipoic acid
  • Citrate Is Kreb's Starting Substrate For Making Oxaloacetate
    • Citrate (Citrate synthase)
    • Isocitrate
    • a- ketoglutarate ( isocitrate dehydrogenase)
    • Succinyl CoA (a-KG dehydrogenase)
    • Succinate
    • Fumarate
    • Malate
    • Oxaloacetate

43

Electron Transport Chain

NADH electrons form glycolysis enter mitochondria via the malate-aspartate or G3P shuttle

  • Complex I: NADH--> NAD+
  • Complex II: FADH2 --> FAD
    • succinate dehydrogenase
    • FADH2 electrons are transfered to complex II

  • Complex III: CoQ
  • Complex IV: 1/2 +2H+ --> H2O
  • Complex V: ADP +Pi --> ATP

44

Electron Transport Chain

ATP production

  • 1 NADH --> 2.5 ATP
  • 1 FADH2 --> 1.5 ATP

45

Electron Chain Inhibitors

  • Complex I: Rotenone
  • Complex III: Antimycin A
  • Complex IV: Cyanide, CO
  • Complex V: Oligomycin

46

Oxidative phosphorylation poisons

  • Electron transport inhibitors:
    • directly inhibit electron transport
    • causing decrease in proton gradient and block of ATP synthesis
  • ATP synthase inhibitors
    • directly inhibit ATP synthase causing an increase in proton gradient
    • No ATP is produced because electron transport stops
  • Uncoupling agents
    • increas permability of membrane
    • causes a decrease in proton gradient
    • increase in O2 consumption
    • electron transport continues
    • produces heat
    • 2,4 Dinitrophenol, aspirin, thermogenin

47

Gluconeogenesis:

Irreversible Enzymes

  • Pyruvate carboxylase
    • mitochrondria
    • Pyruvate --> oxaloacetate
    • requires biotin, ATP
    • activated by Acetyl coA
  • Phosphoenolpyruvate carboxykinase
    • Cytosol
    • Oxaloacetate --> phosphoenolpyruvate
    • requires GTP
  • Fructose 1,6, bisphosphatase
    • cytosol
    • Fruc 1,6BP --> Fru 6P
    • Citrate (+)
    • Fru 2,6 (-)
  • Glucose 6 phosphatase
    • ER
    • G6P --> glucose

48

Gluconeogenesis

  • Occurs primarily in liver to maintain euglycemia during fasting
  • deficiency of key gluconeogenic enzymes cause hypoglycemia
  • Odd chain fatty acid yields 1 propionyl CoA during metabolism which can enter TCA, undergo gluconeogenesis and serve as glucose source

49

HMP shunt

(pentose phosphate pathway)

  • Provides a source of NADPH from G6P
  • NADPH required for reductive reactions
    • glutathione reduction in RBC
    • Fatty acid and cholesterol biosynthesis
  • yields ribose for nucleotide synthesis and glycolytic intermediates
  • occurs in cytoplasm
  • No ATP used or produced
  • Sites
    • lactaing mammary glands
    • liver
    • adrenal cortex ( site of fatty acid or steroid synthesis)
    • RBCs

50

HMP shunt:

Oxidative reaction

Irreversible

  • Glucose 6P --> --> NADPH
    • Glu 6P dehydrogenase
    • Rate limiting
    • requires NADP+
    • Products: CO + 2NADPH +Ribulose 5P

Reversible

  • Ribulose 5 P Ribose 5 P
    • Phosphopentose isomerase, transketolase
    • Requires B1
    • Products: RIbose 5P, G3P, F6P

 

51

Respiratory Burst

(Oxidative Burst)

  • Activation of phagocyte NADPH oxidase (neutrophils, monocytes)
  • utilizes O2 as substrate
  • rapid release of ROS 
  • Phagolysosome
    • NADPH oxidase
    • Superoxide dismutase
    • myeloperoxidase
    • Glutathionine peroxidase ( requires selenium)
    • Glutathionine reductase (requires selenium)
    • G6PD

52

Chronic Granulomatous Disease

  • Deficiency in NADPH oxidase
  • can use H2O2 generated by invading organisms and convert it to ROS
  • increase risk for infections by catalase (+) species
    • S.aureus, Aspergillus capapble of neutralizing their own H2O2
    • phagocytes have no ROS for fighting infections

53

Respiratory burst (oxidative phosphorylation) Reactions

  • O2
  • O2- (Superoxide) [ NADPH oxidase]
  • H202 [Superoxide dismutase]
  • HOCl (hypochlorite) [Myeloperoxidase]​

Bacterial catalase

  • H2O2--> H20 + O2

Glutathione peroxidase

  • H202 --> H20
  • GSH (reduced) --> GSSG

54

G6PD dehydrogenase deficiency

  • NADPH is necessary to keep glutathione reduced
  • Glutathione detoxifies free radicals and peroxides
  • decreased in NADPH in RBC= hemolytic anemia
    • oxidizing agents: fava beans, sulfonamides, primaquine, anti-TB drugs
    • infection can also precipitate hemolysis
  • X-linked recessive
  • increased malarial resistance
  • Heinz bodies= oxidized Hemoglobin precipitated in RBC
  • Bite cells: phagocytc removal of Heinz bodies by splenic macrophages

55

Essential Fructosuria

  • defect in fructokinase
  • autosomal recessive
  • benign, asymptomatic condition
  • Sxs: fructose appears in urine and blood

56

Fructose intolerance

  • Hereditary deficiency of Aldolase B
  • autosomal recessive
  • Fructose -1-P accumulates causing decrease in available phosphate
  • inhibits glycogenolysis and gluconeogenesis
  • Sxs: present with consumption of fruit, juice, honey
    • hypoglycemia, jaundice, cirrhosis, vomiting
  • Urine dipstick will be negative
    • reducing sugar can be detected in urine
  • Tx: decrease intake of fructose and sucrose

57

Metabolism of Fructose

  • Fructose
  • Fru 1 P [Fructokinase]
    • Dihydroxyacetone-P  [aldolase B]
    • Glyceraldehyde [aldolase B]
      • Glyceraldehyde 3P [Triose kinase]
  • Glyceraldehyde 3p --> glycolysis

58

Galactokinase Deficiency

Hereditary deficiency of galactokinase

  • Galacititol accumulates if galactose is present
  • autosomal recessive
  • Sxs: galactose appears in blood and urine, infantile cateracts
  • May present intially as failure to track objects or develop a social smile

59

Classic Glactosemia

Absence of galactose-1-P uridyltransferase

  • Galactose 1p --> Glucose 1 P 
    • [Uridyltransferase]
  • autosomal recessive
  • accumulation of toxic substances
    • galacititol accummulates in lens of eye
  • Sxs: failure to thrive, jaundice, hepatosplenomegaly, infantile cateracts, intellectual disability
  • Tx: exclude galactose and lactose from diet
  • Can lead to neonatal sepsis in neonates

60

Sorbitol

  • alternative method of trapping glucose in cell is to convert it to its alcohol counterpart, sorbitol
  • some tissues convert sorbitol to fructose [sorbitol dehydrogenase]
  • Tissues with insufficienct enzyme can accumulate sorbitol causing osmotic damage
    • cataracts, retinopathy, peripheral neuropathy in chronic hyperglycemia
  • high levels of galataose also results in conversion to galactitol [aldose reductase]

61

Lactase Deficiency

Insufficiency lactase enzyme

  • Dietary lactose intolerance
  • lactase digests lactose into glucose and galactose
  • Primary: age dependant decline after childhood
  • Secondary: loss of brush border due to gastroenteritis (rotovirus), autoimmune disease
  • Congenital: rare due to defective genes
  • Stool: decreased pH
  • Breath: increase hydrogen content
  • intestinal biopsy reveals normal mucosa in patients with hereditary lactose intolerance
  • FIndings: bloating, flatulence, osmotic diarrhea
  • tx: avoid dairy products, lactase pills, 

62

Essential Amino Acids

  • Glucogenic:
    • Methionine (Met)
    • Valine (val)
    • Histidine (His)
  • Glucogenic/ketogenic
    • isoleucine (Ile)
    • phenylalanine (Phe)
    • Threonine (thr)
    • Tryptophan (Trp)
  • Ketogenic
    • Leucine (Leu)
    • Lysine (lys)

63

Acidic Amino acids

  • Aspartic acid (Asp)
  • Glutamic acid (glu)
  • negatively charged at body pH

64

Basic Amino Acids

  • Arginine (arg)-- most basic
  • Lysine (lys)
  • Histidine (his)-- no charge at body pH
  • Arg and His are required during periods of growth
  • Arg and lys are increased in histones which bind negatively charged DNA

65

Urea Cycle

amino acid catabolism

  • Forms pyruvate, acetyl-coA for metabolic fuel
  • Ordinarily, Careless Crappers Are Also Frivolous about Urination
    • Ornithine + Carbamoyl phosphate
    • Citrulline [ ornithine transcarbamylase]
    • + Aspartate--> Argininosuccinate [ Argininosusccinate synthetase]
    • Fumarate + Arginine [Argininosuccinase]
    • Urea + Ornithine [Arginase]
  • Carbamoyl phosphate synthetase
    • makes carbamoyl phosphate
    • requires N-acetylglutamate

66

Transport of Ammonia

Muscle 

  • Amino acids (NH3) --> a- ketoacids
  • A-ketoglutarate--> Glutamate (NH3)
  • Glutamate (NH3)--> a-ketoglutarate
  • Pyruvate--> alanine (NH3)

Liver

  • alanine (NH3) --> pyruvate
    • a-ketoglutarate --> glutamate (NH3) --> urea (NH3)
  • Pyruvate --> glucose (transported to muscle)

Muscle

  • Glucose --> pyruvate--> lactate (Cori cycle)

67

Hyperammonemia

Results in excess NH4+

  • depletes a-ketoglutarate
  • inhibits TCA cycle
  • Tx: limit protein in diet
  • Benzoate or pehnylbutyrate can be given to decrease ammonia levels
  • Lactulose can acidify GI tract and trap NH4+ for excretion
  • Sxs: tremor (asterixis, slurring of speech, somnolence, vomiting, cerebral edema, blurring of vision)

68

N-acetylgutamate Deficiency

  • Required co-factor for carbamoyl phosphate synthetase I in Urea cycle
  • Increased ornithine in urea cyce suggests hereditary deficiency

69

Ornithine Transcarbamylase deficiency

  • Most common urea cycle disorder
  • x-linked
  • inability to eliminated ammonia
  • excess carbamoyl phosphate is converted to orotic acid
  • Findings: increased orotic acid in blood and urine, decreased BUN, sx of hyperammonia
  • no megaloblastic anemia (vs orotic aciduria)

70

71

Amino Acid derivatives:

Phenylalanine

  • Thyrosine (BH4)
    • Thyroxine
  • --> Dopa (BH4)
    • Melanine
  • --> Dopamine (B6)
  • --> NE (vitamin C)
  • --> Epi (SAM)

72

Amino Acid derivatives:

Tryptophan

  • Niacin (B6)
    • NAD/NADP+
  • Serotonin (BH4, B6)
    • Melatonin

73

Amino Acid derivatives:

Histidine

  • Histamine (B6)

74

Amino Acid derivatives:

Glycine

  • Porphyrin (B6)
    • Heme

75

Amino Acid derivatives:

Glutamate

  • GABA (B6)
  • Glutathionine

76

Amino Acid derivatives:

Arginine

  • Creatinine
  • Urea
  • Nitric Oxide (BH4)

77

Phenylketouria

Decreased phenylalanine hydroxylase or tetrahydrobiopterin (BH4)

  • Increase in phenylalanine lees to excess phenylketones in urine
    • phenylketones ( phenylacetate, phenylactate, phenylpyruvate)
  • Autosomal recessive
  • screened for 2-3 days after birth ( maternal enzyme during birth)
  • Disorder of aromatic amino acid metabolism--> musty body odor
  • Findings: intellectual disability, growth retardation, seizures, fair skin, eczema, musty body ordor
  • Must avoid aspartame (contains phenylalanine)
  • Tx: decrease phenylalanine and increase tyrosine in diet

78

Maternal PKU

lack of proper dietary therapy during pregnancy

  • Infant findings
    • microcephaly
    • intellectural disability
    • growth retardation
    • congenital heart defects

79

Alkaptouria

(Ochronosis)

Congenital deficiency of homogentisate oxidase in the degradative pathway of tyrosine into fumarate

  • Autosomal recessive
  • Benign disease
  • Findings
    • dark connective tissue, brown pigmented sclera, urine turns black on prolonged exposure to air
    • may have debilitating arthralgias (homogentisic acid toxic to cartilage)

80

Homocysttinuria

Excess homocysteine

  • Findings
    • increase in homocysteine in urine, intellectual disability, osteoporosis, tall stature, kyphosis, lens subluxation, thrombosis, atherosclerosis (stroke, MI)
  • Homocysteine--> Methionine
    • Homocysteine methyltransferase & B12
  • Homocysteine --> Cystathionine--> Cysteine
    • Cystathionine synthase & B6

Types

  • Cysthathionine Synthase deficiency
    • tx: decrease methionine, increase cysteine, increase B12 and folate in diet
  • Decreased affinity of cysthathionine synthase for pyridoxal phosphate
    • Increase B6 and cysteine in diet
  • Homocysteine methyltransferase deficiency
    • tx: increase methionine in diet

81

Cystinuria

Hereditary defect of renal PCT and intestinal amino acid transported for Cysteine, Ornithine, Lysine and Arginine (COLA)

  • Excess cystine in urine can lead to precpitatinof hexagonal cystine stones
  • Autosomal recessive
  • Urinary cyanide-nitroprusside test is diagnostic
  • Tx:
    • Urinary alkalizination (potassium citrate, acetazolamide)
    • Chelating agents increase solubility of cystine stones
    • Good hydration
    •  

82

Maple Syrup Urine disease

Blocked degradation of brached amino acids

(Isoleucine Leucine, Valine)

  • Dereased alpha-ketoacid dehydrogenase
  • increases alpha-ketoacid in blood
  • Autosomal recessive
  • Urine smells like burnt sugar/ maple syrup
  • Tx: restriction of leucine, isoleucine, valine in diet

83

Glycogen regulation

Glycogen --> glucose

  • Glycogen phosphorylase

Glucose --> Glycogen

  • Glycogen synthase

 

Regulators

  • Glucagon: binds glucagon R (liver)
    • increase cAMP --> PKA
    • Activates Glycogen Phosphorylase Kinase
    • Activates Glycogen phosphorylase
  • Epi: Binds Beta receptors (liver, muscle)
    • increase cAMP--> PKA
    • activates glycogen phosphorylase kinase
    • activates glycogen phosphorylase
  • Epi: binds alpha- receptors (liver)
    • increase Ca release from ER
    • activates glycogen phosphorylase kianse
    • activates glycogen phosphorylase
  • Insulin: Binds tyrosine kinase dimer R (liver, muscle)
    • activates Glycogen Synthase
      • inhibited by PKA
    • Activates protein phosphatase ( inhibits glycogen Phosphorylase)

84

Glycogen

  • Structure:
    • branches have a (1,6) bonds
    • Linkages have a (1,4) bonds
  • Skeletal muscle
    • Glycogen undergoes glycogenolysis
    • glucose 1 P--> glucose 6P ( exercise)
  • Hepatocytes
    • Glycogen is stored and undergoes glycogenolysis to maintain blood sugars
    • Glycogen phosphorylase cleaves Glu1P residues off until 4 remain (limit dextrin)
    • 4-alpha-glucanotransferase (debranching enzyme) mvoes three Glu1P from one branch to the linkage
    • A-1,6 glucosidase cleaves off last Glu1P on branch

85

Glycogen Storage Diseases

  • von Gierke disease ( Type I)
  • Pompe disease ( Type II)
  • Cori Disease (Type III)
  • McArdle disease ( Type IV)

86

Von Gierke Disease

  • Accumulation of glycogen in cells
  • Severe fasting glucose, increase glycogen in liver, increase blood lactate, hepatomegaly
  • Deficiency in Glucose 6 phosphatase
  • Autosomal recessive
  • Tx: Frequent oral glucose/ cornstarch, avoid fructose and galactose

87

Pompe Disease

  • Accumulation of glycogen
  • Cardiomyopathy
  • leads to early death
  • Deficiency: lysosomal a 1,4, glucosidase ( acid maltase-- degradation of glycogen in lysosome)
  • Autosomal recessive

88

Cori Disease

  • Glycogen storage disease
  • Milder form of von Gierke sxs ( fasting hypoglycemia, increase glycogen in liver, normal blood lactate levels)
  • Deficiency: Debranching enzyme ( a 1,6 glucosidase)
  • Autosomal recessive
  • Gluconeogenesis is intact

89

McArdle Disease

  • Glycogen storage disease
  • increase glycogen in muscle but can't break it down
  • muscle cramps. myoglobinuria (red urine) with strenuous exercise, arrhythmia from electrolyte abnormalities
  • Deficiency: skeletal muscle glycogen phosphorylase
  • Autosomal recessive

90

Lysosomal Storage Disease

Caused by deficiency of lysosomal enzymes and leads to accumulation of abnormal metabolites

Sphingolipidoses

  • Fabry disease
  • Gaucher disease
  • Niemann-Pick disease
  • Tay-Sachs disease
  • Krabbe disease
  • Metachromatic leukodystrophy

Mucopolysaccharidoses

  • Hurler syndrome
  • Hunter syndrome

91

Fabry Disease

  • Lysosomal storage disease
  • Peripheral neuropathy of hands/ feet, angiokeratoma, cardiovascular/ renal disease
  • Deficiency: Alpha-galactosidase A
  • Accumulated substrate: Cermide trihexoside
  • X-linked Recessive

92

Gaucher disease

  • Lysosomal Storage disease
  • Hepatosplenomegaly, pancytopenia, aseptic necrosis of femur, bone crieses
  • Gaucher cells ( lipid laden macrophage that resembles crumpled tissue paper)
  • Deficiency: Glucocerebrosidase ( B-glucosidase)
  • Accumulated substrate: Glucocerebroside
  • Tx: recombinant glucocerebrosidase
  • Autosomal recessive

93

Niemann-Pick disease

  • Lysosomal Storage disease
  • Progressive neurodegeneration, hepatosplenomegaly, "cherry-red spot" on macula
  • foam cells (lipid laden macrophages)
  • Deficiency: Sphingomyelinase
  • Accumulated substrate: Sphongomyelin
  • Autosomal recessive

94

Tay Sachs Disease

  • Lysosomal storage disease
  • progressive degeneration, developmental delay, cherry-red spot on macula, lysosomes with onion skin
  • no hepatosplenomegaly ( vs. Niemann-pick)
  • Deficiency: Hexoaminidase A
  • Accumulated substrate: GM2 ganglioside
  • Autosomal recessive

95

Krabbe Diseas

  • Lysosomal Storage disease
  • Peripheral neuropathy, developmental delay, optic atrophy, globoid cells
  • Deficiency: Galactocerebrosidase
  • Accumulated substrate: glalactocerebroside, psychosine
  • Autosomal recessive

96

Metachromatic leukodystrophy

 

  • Lysosomal storage disease
  • Cenral and peripheral demyelination with ataxia, dementia
  • Deficiency: Arylsulfatase A
  • Accumulated substrate: Serebroside sulfate
  • Autosomal Recessive

97

Hurler Syndrome

  • Lysosomal storage disease
  • Developmental delay, gargoylism, airway obstruction, corneal clouding, hepatosplenomegaly
  • Deficiency: a-L-iduronidase
  • Accumulated substrate: Heparan sulfate, dermatan sulfate
  • Autosomal recessive

 

98

Hunter Syndrome

  • Lysosomal Storage disease
  • Mild Hurler sxs: devo delay, gargoylism, airway obstruction, heptosplenomegaly, with aggressive behavior
  • Deficiency: Iduronate sulfatase
  • Accumulated substrate: Heparan Sulfate, dermatan sulfate
  • X-linked recessive

99

Carnitine Deficiency

  • Long chain fatty acid degradation requires carnitine-dependant transport into mitchondrial matrix
  • Deficiency: inability to transport LCFA into mitochondria resulting in toxic accumulation
  • Causes weakness, hypotonia, hypoketotic hypoglycemia

100

Acyl CoA dehydrogenase deficiency

  • Increase dicarboxylic acids
  • decrease glucose and ketones
  • decreased acyl-coA--> decrease fasting glucose

101

Long Chain Fatty Acids Synthesis

  • Citrate (citrate shuttle:  mito --> cyto)
  • Acetyl-coA ( ATP citrate lyase)
  • Malonyl Co-A
  • Fatty acid synthesis ( Palmitate)

102

Long chain FA degradation

  • Fatty acid + CoA
  • Acetyl CoA ( Fatty acid CoA Synthetase)
  • Carnitine Shuttle ( Cyto to mitochondria)
  • Beta- oxidation of acyl CoA to acetyl CoA groups
    • Ketone bodies
    • TCA cycle

103

Ketone Bodies

  • Liver
  • Fatty acids and amino acids are metabolized to acetoacetate and B-hydroxybutyrate
  • breath smells like acetone ( fruity)
  • Urine test does not detect B-hydroxybutyrate
  • Prolonged starvation, diabetic ketoacidosis
    • oxaloacetate is depleted for gluconeogenesis
  • Alcoholism
    • excess NADH shunts oxaloacetate to malate
  • Leads to build of acetyl-CoA
    • shunts glucose and FFA to production of ketone bodies

104

Fasting and Starvation

  • Fed state
    • Glycolysis and aerobic respiration
    • Insulin stimulates storage of lipids, proteins, fats
  • Fasting (in between meals)
    • Hepatic glycogenolysis
    • Hepatic gluconeogenesis
    • Adipose release of FFA
    • Glucagon, adrenaline stimulates use of fuel reserves
  • Starvation (1-3 days)
    • Hepatic glycogenolysis
    • Adipose release FFA
    • Muscle and liver shift fuel use from glucose to FFA
    • Hepatic gluconeogenesis from tissue lactate and alanine & from adipose tissue glyerol and propionyl coA (odd chain FA)
    • Glycogen reserves depleted after 1 day
  • Starvation after day 3
    • Adipose stores (ketone bodies) become main source of energy for brain
    • after depletion, vital protein degradation occurs leading to organ failure and death

105

Cholesterol Synthesis

  • Rate limiting step: HMG-CoA reductase
    • induced by insulin
    • HMG-CoA --> mevalonate
    • 2/3 of plasma cholesterol is esterified by lecithin-cholesterol acyltransferase (LCAT)
  • Statin competitively and reversibly inhibit HMG-CoA reductase

106

Lipid Transport

  • Dietary fat & cholesterol absorbed from intestine
  • Chylomicrons transport lipids
    • LDL: lipoprotein lipase degrades TG circulating in chylomicrons to FFA and remnants
  • FFA
    • is stored in adipose 
    • take up by peripheral tissues with LDL Receptors
  • Chylomicron remnants
    • take up by liver
  • Liver synthesizes VLDL ( delivery to tissues)
    • LPL degrades TG in VLDL to form FFA and IDL
    • IDL is degraded by Hepatic Lipase (TG) to LDL
  • IDL is take up by hepatic LDL R

107

Cholesterol Transport

  • Liver/ intestine make nascent HDL
  • LCAT catalyzes the esterification of cholesterol to mature HDL
  • Cholesterol ester transfer protein (CETP) transfers cholesterol esters to VLDL, IDL, LDL

108

Apolipoproteins

  • E: mediates remnant uptake
    • chylomicrons, chylomicron remnant, VLDL, IDL, HDL
  • AI: activates LCAT
    • chylomicron, VLDL, HDL
  • CII: Lipoprotein lipase cofactor
    • Chylomicrons, VLDL, HDL
  • B48: mediates chylomicron secretion
    • Chylomicron, chylomicron remnant
  • B100: binds LDL receptor
    • VLDL, IDL, LDL

109

Lipoprotein functions

  • Composed of cholesterol,  TG, phospholipids
  • LDL: transport cholesterol from liver to tissues
  • HDL: transport cholesterol from periphery to liver

110

Chylomicron

  • apolipoproteins: E, AI, CII, B48
  • delievers TG to peripheral tissues
  • delievers choelsterol to liver in form of chylomicron remnants
  • secreted by intestinal epithelial cells

111

VLDL

  • Apolipoproteins: E, CII, B100
  • Delievers hepatic TG to peripheral tissues
  • Secreted by the liver

112

IDL

  • Apolipoproteins: E, B100
  • Formed in the degradation of VLDL
  • Delivers TG and cholesterol to liver

113

LDL

  • apolipoproteins: B100
  • delivers hepatic cholesterol to peripheral tissues
  • formed by hepatic lipase modification of IDL in peripheral tissue
  • taken up by cells via receptor mediated endocytosis

114

HDL

  • Apoplipoproteins: E, A1, CII
  • mediates reverse cholesterol transport from periphery to liver
  • acts as repository for apoC and ApoE ( for chylomicron and VLDL metabolism)
  • Secreted from liver and intestine
  • alcohol increase synthesis

115

Hyper chylomicronemia

Type I familial dyslipidemia

 

  • Deficiency: Lipoprotein Lipase or altered CII
  • Autosomal recessive
  • increased: chylomicrons, TG, cholesterol
  • causes pancreatitis, hepatosplenomegaly, eruptive/ pruritic xanthoma

116

Familial Hypercholeterolemia

Type IIA familal dyslipidemia

  • absent or defective LDL receptor
  • Increased: Cholesterol, LDL
  • Autosomal Dominant
  • Accelerated atherosclerosis
    • may have MI before age 20
    • tendon (achilles) xanthoma
    • corneal arcus

117

Hyper Triglyceridemia

Familial Dyslipidemia Type IV

  • Hepatic overproduction of VLDL
  • Increased: VLDL, TG
  • Autosomal Dominant
  • Causes pancreatitis

118

S. Aureus

  • Gram positive
  • Catalase positive
  • Cluster
  • Cocci

119

Staphylococcus Epidermidis

  • Novobiocin sensitive
  • Coagulase negative
  • Catalase Positive
  • Cocci
  • Gram +

120

Staphylococcus saprophyticus

  • Novobiocin resistant
  • coagulase negative
  • catalase positive
  • Cocci
  • Gram positive

121

Streptococcus Pneumoniae

  • Capsule
  • optochin sensitive
  • bile soluble
  • alpha hemolysis
  • Catalase negative
  • cocci, chains
  • Gram positive

122

Viridans streptococci:

S. mutans

  • no capsule
  • optochin resistant
  • bile insoluble
  • alpha hemolytic
  • cocci, chains
  • Gram +

123

Streptococcus pyogenes

  • Bacitracin sensitive
  • Beta hemolytic
  • cocci, chains
  • catalase negative
  • Group A strep
  • Gram positive

124

Stretococcus agalactiae

  • Group B strep
  • Bacitracin resistant
  • Beta hemolysis
  • catase negative
  • cocci, chains
  • gram positive

125

Enterococcus

  • Group D
  • Growth in bile and 6.5% NaCl ( E. faecalis)
  • gamma hemolytic ( no hemolysis)
  • catase negative
  • cocci, chains
  • Gram positive

126

Streptococcus Bovis

  • non-enterococcus
  • grows in bile
  • does not grow in 6.5% NaCl
  • Gamma hemolytic ( no growth)
  • Catalase negative
  • chains, cocci
  • gram positive

127

Actinomyces

  • Anaerobe
  • not acid fast
  • branching filaments gram positive

128

Nocardia

  • aerobe
  • acid fast
  • branching filaments
  • gram positive

129

alpha hemolytic

  • Strep pneumoniae
  • Viridans streptococci ( S. mutans)

130

Beta hemolytic

Forms clear areas of hemolysis on blood agar

  • Staphylococcus aureus
  • Streptococcus pyogenes
  • Streptococcus agalactiae
  • Listeria monocytogenes

131

Neisseria Meningitidis

  • Maltose fermenter
  • Diplococci
  • Gram negative

132

Neisseria gonorrheae

  • maltose non-fermenter
  • diplococci
  • gram negative

133

Gram negative: Coccoid rods

  • H. influenzae
  • pasteurella
  • Brucella
  • Brodetella pertussis

134

Gram negative: Rods

Fast Lactose fermenters

  • Klebsiella
  • E. Coli
  • Enterobacter

135

Gram negative

Rod

Slow Lactose fermenter

  • Citrobacter
  • Serratia

136

Gram negative

Rods

Lactose non-fermenter

Oxidase negative

  • Shigella
  • salmonella
  • proteus
  • yersinia

137

Gram negative

Rods

Lactose non-fermenter

Oxidase positive

Pseudomonas

138

Campylobacter jejuni

  • Grows in 42C
  • oxidase positive
  • comma shaped
  • gram negative

139

Vibrio Cholerae

  • Grows in alkaline media
  • oxidase positive
  • common shaped
  • gram negative

140

Helicobacter pylori

  • produces urease
  • oxidase positive
  • comma shaped
  • gram negative

141