Biochemistry - Metabolism II

Each is caused by a deficiency of one of the many lysosomal enzymes

Results in an accumulation of abnormal metabolic products

• Types:
• -Sphingolipidoses
• -Mycopolysaccharidoses

• Sphingolipidoses:
• -Fabry's Disease
• -Gaucher's Disease
• -Niemann-Pick Disease
• -Tay-Sach's Disease
• -Krabbe's Disease
• -Metachromatic Leukodystrophy

• Mucopolysaccharidoses
• -Hurler's Syndrome
• -Hunter's Syndrome

• Inheritance:
• -X-linked recessive

• Deficient Enzyme
• -α-galactosidase A

• Accumulated Substrate:
• -ceramide trihexoside

• Findings:
• -perihperal neuropathy of hands/feet
• -angiokeratomas
• -cardiovascular disease
• -renal disease

• Inheritance:
• -autosomal recessive

• Deficient Enzyme:
• -Glucocerebrosidase

• Accumulated Substrate:
• -glucocerebroside

• Findings:
• -most common lysosomal storage disease
• -hepatosplenomegaly
• -aspetic necrosis of femur
• -bone crises
• -Gaucher's cells (macrophages that look like crumpled tissue paper)
• 

• Inheritance:
• -autosomal recessive

• Deficient Enzyme:
• -Sphigomyelinase

"No man picks (Neimann-Pick) his nose with his sphinger (sphingomyelinase)"

• Accumulated Substrate:
• -Spingomyelin

• Findings:
• -progressive neurodegeneration
• -hepatosplenomegaly
• -cherry-red spot on macula
• -foam cells
• 
• *death in early childhood

• Inheritance:
• -autosomal recessive

• Deficient Enzyme:
• -Hexosaminidase A

"Tay-SaX lacks heXosaminidase"

• Accumulated Substrate:
• -GM2 Ganglioside

• Findings:
• -progressive neurodegeneration
• -developmental delay
• -cherry-red spot on macula
• -lysosomes with onion skin
• -no hepatosplenomegaly (vs Neimann-Pick)
• *death in early childhood

• Inheritance:
• -autosomal recessive

• Deficient Enzyme:
• -Galactocerebrosidase

• Accumulated Substrate:
• -Galactocerebroside

• Findings:
• -peripheral neuropathy
• -developmental delay
• -optic atrophy
• -globoid cells
• *death in early childhood

• Inheritance:
• -autosomal recessive

• Deficient Enzyme:
• -Arylsulfatase A

• Accumulated Substrate:
• -Cereroside sulfate

• Findings:
• -central and peripheral demyelination
• -ataxia
• -dementia

• Inheritance:
• -autosomal recessive

• Deficient Enzyme:
• -α-L-iduronidase

• Accumulated Substrate:
• -heparan sulfate, dermatan sulfate

• Findings:
• -developmental delay
• -gargoylism
• -airway obstruction
• -corneal clouding
• -hepatosplenomegaly

**Scheie's is a milder form of hurler's

• Inheritance:
• -X-linked recessive

• Deficient Enzyme:
• -Iduronate sulfatase

• Accumulated Substrate:
• -heparan sulfate, dermatan sulfate

• Findings:
• -mild Hurler's
• - + aggressive behaviour
• -no corneal clouding

"Hunters see clearly (no corneal clouding) and aim from the X (X-linked recessive)"

• Increased incidence of:
• -Tay Sachs
• -Niemann Pick
• -some forms of Gauchers

*Fatty acid degradation occurs where its products will be consumed: in the mitochondrion

• FA + Co-A → Acyl-CoA → β-oxidation → Acetyl-CoA (can go onto ketone bodies or TCA cycle)
• -uses Carnitine Shuttle

• Important Enzymes:
• -Fatty acid CoA synthetase

"CARnitine = CARnage of fatty acids"

Citrate is transferred from the mitochondrial matrix to the cytoplasm by the citrate shuttle

Citrate → Acetyl-CoA → Malonyl CoA → FA synthesis

Malonyl CoA and Acetyl CoA are combined by fatty acid synthase into palmitate (16C FA)

• Important Enzymes:
• -ATP citrate lyase (citrate → Acetyl CoA)
• -Fatty Acid Synthase

• "SYtrate" = SYnthesis
• 

• Pathophysiology:
• -inability to transfer LCFAs into the mitochondria
• -results in toxic accumulation of LCFAs

• Presentation:
• -weakness
• -hypotonia
• -hypoketotic hypoglycemia

• Findings:
• -↑ Dicarboxylic Acids
• -↓ Glucose and Ketones

• In the liver, FAs and AAs are metabolized to acetoacetate and β-hydroxybutyrate
• -used in muscle and brain

• Prolonged starvation/DKA:
• -oxaloacetate is depleted for gluconeogenesis

• Alcoholism:
• -excess NADH shunts oxaloacetate to malate

• BOTH STALL THE TCA:
• -shunts glucose and FFAs toward the production of ketone bodies

• Presentation:
• -breath smells like acetone (fruity odor)
• -urine tests for ketones do not detect β-hydroxybutyrate (favored by high redox state)
• Important Enzymes:
• -HMG-CoA synthase
• -HMG-CoA lyase

• Metabolism:
• -in brain, metabolized to 2 molecules of acetyl-CoA
• -excreted in urine
• 

• Stored ATP:
• -used within seconds

• Creatine Phosphate:
• -synthesized (released?) and used within seconds

• Anaerobic Glycolysis:
• -generates energy over minutes, up to hours

• Aerobic metabolism and FA Oxidation:
• -generate ATP initially more slowly (start working around minutes)
• -around hours increases production (major source)

• 1g protein or carbohydrate = 4kcal
• 1g fat = 9kcal

• -supply sufficient glucose to brain and RBCs
• -preserve protein

• Processes:
• -Glycolysis
• -Aerobic Respiration

• Regulation:
• -insulin stimulates storage of lipids, proteins and glycogen

• Processes:
• -hepatic glycogenolysis (major)
• -hepatic gluconeogenesis
• -adipose release of FFA (minor)

• Regulation:
• -glucagon/adrenaline stimulate use of fuel reserves

• Blood Glucose Level Maintained By:
• -hepatic glycogenolysis
• -adipose release of FFA
• -muscle and liver shift fuel use from glucose to FFA
• -hepatic gluconeogenesis from peripheral tissue lactate and alanine
• -hepatic gluconeogenesis from adipose tissue glycerol and propionyl-CoA (from odd chain FFA: the only TG components that contribute to gluconeogenesis)

• Regulation:
• -Glycogen reserves deplete after day 1
• **RBCs lack mitochondria and so cannot use ketones

• Processes:
• -Adipose stores (ketones bodies become the main source of energy for the brain and heart)
• -after these are depleted, vital protein degradation accelerates leading to organ failure and death)

**Amount of adipose stores determines survival time

-occurs in the liver and intestinal mucosa

• Important Enzymes:
• -HMG-CoA reductase (rate-limiting step)
• -converts HMG-CoA to mevalonate

**2/3 of plasma XOL is esterified by lecithin-cholesterol acyltransferase (LCAT)

**Statins inhibit HMG-CoA Reductase

1. Dietary fat and XOL is absorbed at the small intestine

2. Intestinal epithelial cells produce chylomicrons which are then secreted into the blood stream

3. Chylomicrons TG is hydrolyzed to FFA by LPL on the surface of capillary endothelium (muscle and adipose tissue)

4. FFAs are incorporated into adipose tissue and muscle

5. Chylomicron remnants travel to the liver and are taken up by remnant receptors

6. Liver synthesizes vLDL

7. vLDL is hydrolyzed by LPL to FFA and IDL

6. FFA are taken up by adipose tissue and peripheral tissues with LDL receptors

7. IDL can be reabsorbed by the liver (using LDL receptors) or converted to LDL by HL

8. LDL is taken up into muscle cells or the liver by LDL receptors

• Important Enzymes:
• -Pancreatic Lipase: degradation of dietary TG in small intestine
• -Lipoprotein Lipase (LPL): degradation of TG circulating in chylomicroms and vLDLs
• -Hepatic TG Lipase (HL): degradation of TG remaining in IDL
• -Hormone-sensitive lipase: degradation of TG stored in adipocytes

• Lecithin-cholesterol acyltransferase (LCAT)
• -catalyzes esterification of XOL

• Cholesterol ester transfer protein (CETP)
• -mediates transfer of XOL esters to other lipoprotein particles

Lipoproteins are composed of various proportions of XOL, TGs and phospholipids

LDL and HDL carry most of the cholesterol

• LDL transports XOL from liver to tissues
• "LDL is Lousy"

• HDL transports XOL from periphery to liver
• "HDL is Healthy"
• Types:
• -Chylomicron
• -vLDL
• -IDL
• -LDL
• -HDL

• Function:
• -delivers dietary TGs to peripheral tissue
• -delivers XOL to the liver in the form of chylomicron remnants (which are mostly depleted of the TGs)

Secreted by intestinal epithelial cells

• Function:
• -delivers hepatic TGs to peripheral tissue

Secreted by liver

• Functions:
• -delivers TGs and XOL to liver

Formed in the degradation of vLDL

• Function:
• -delivers hepatic XOL to peripheral tissues
• -taken up by target cells via receptor-mediated endocytosis

Formed by hepatic lipase modification of IDL in the peripheral tissue

• Function:
• -mediates reverse XOL transport from periphery to liver
• -acts as a repository for apoC and apoE (needed for chylomicron and vLDL metabolism)

Secreted from both liver and intestine

• 1. I: hyperchylomicronemia
• 2. IIA: familial hypercholesterolema
• 3. IV: hyper-triglyceridemia

• Pathophysiology:
• -autosomal recessive
• -lipoprotein lipase (LPL) deficiency or altered apoplipoprotein C-II

• Presentation:
• -pancreatitis
• -hepatosplenomegaly
• -eruptive/pruritic xanthomas (no increased risk for atherosclerosis)

• Increased Blood Level:
• -chylomicrons
• -TG
• -XOL

• Pathophysiology:
• -autosomal dominant
• -absent or decreased LDL receptor

• Presentation:
• -accelerated atherosclerosis
• -tendon (achilles) xanthomas
• 
• -corneal arcus
• 

• Increased Blood Level:
• -LDL
• -XOL

• Pathophysiology:
• -autosomal dominant
• -hepatic overproduction of vLDL

• Presentation:
• -pancreatitis

• Increased Blood Level:
• -vLDL
• -TG

• Pathophysiology:
• -autosomal recessive
• -mutation in microsomal TG transfer protein (MTP)
• -leads to decreased B-48 and B-100
• -leads to decreased chylomicron and vLDL synthesis and secretion

• Presentation:
• -symptoms appear within the first months of life
• -intestinal bx: lipid accumulation in enterocytes (inability to excrete absorbed lipids as chylomicrons)
• -failure to thrive
• -steatorrhea
• -acanthocytosis
• -ataxia
• -night blindness