Biochem Post Midterm Facts

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reaction of heme oxygenase

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heme->biliverdin
oxygen at methyne group bridge between ring 1 and 2
Fe2+->Fe3+, reduction with NADPH
loss of CO and Fe3+

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heme from macrophage to gut

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in macrophage: heme-biliverdin-bilirubin via heme oxygenase and reductase
transport to liver via albumin
at liver, entry via facilitated diffusion
in liver binding to ligandin and conversion to biliubin diglucuronide with addition of glucuronic acid via UDP-gluronic acid and bilirubin glucuronyl transferase
excretion to bile-active transport
in gut-removal of glucuronide by b-glucuronide bacteria
formation of urobilinogen, steroclobin, back to liver for reabsorption, to kidney and urine- yellow color and urobilin

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HSL

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enzyme in adipose tissue reposinble for fat lipolysis upon stimulation from epinepherine
breaks down fat to glycerol and NEFA.
glycerol will go to the liver while NEFAs will bind to albumin and go to extrahepatic cells for mobilization
stimulated by epinepherine- phosphorylated
inhibited by insulin- dephosphorylated

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LPLases

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These lipases will hydrolyze fats in the blood to glycerol and NEFAS

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ACTIVATED NEFAS

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Transfer of CoA group to Acyl group to make Acyl-CoA: thiokinase

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- Carnitine shuttle

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(cytosol) acyl-CoA->acyl-carnitine ///Acyl-carnitine->Acyl-CoA
(in mito)inactivated by INSULIN, FED state when F.A.Synthesis is in progress
o – inactivated by malonyl CoA

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enzymes and moieties of carnitine shuttle

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CPT 1, CPT 2, acyl-carnitine translocator, OCN2 transporter

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Carnitine Deficiencies

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 whenever there is some sort of impingement in the process of fatty acid oxidation, NEFAS and TAGS cannot be mobilized and cannot be used for energy
 the person is already in a starved state, and the body is trying to utilize gluconeogenesis here too, but will have NO ENERGY from FAO to use in gluconeogenesis as this is an energy requiring process

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typical symptoms of carnitine deficiencies

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• present in infancy, hepatomegaly, cardiomyopathy, general muscle weakness
• patients will present as hypoketonic and hypoglyceamic

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 CPT 1 deficiency

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• Affects liver
• Reduced fatty acid oxidation
• Hypoketonic, no ketone bodies
• Hypoglycemic, low blood sugar

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 CPT 2 deficiency

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• Skeletal and cardiac muscle
• Cardiomyopathy, muscle pain, cramps following prolonged exercise- because no TAGS to synthesize
• Muscle necrosis, myoglobinuria
• Diagnosis is fibroblasts and enzymes
• High CHO low fat diet…want to utilize glucose not FAT

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 Acyl carnitine translocase

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 Acyl carnitine translocase
• Muscle weakness, hypoglycemic, hyperammonoaemic, cardiomyopathy
• FATAL during first few years of life
• No ATP->compromised urea cycle

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 Plasma membrane OCN transporter, • Myopathic carnitine deficiency (Muscle)

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o Autosomal recessive 1 in 100,000 births in Europe and USA
o GENE mutation in OCTN-2
o Defective sodium-dependent transport membrane protein
 Transports carnitine into cytosol of muscle and heart cells
o Low intracellular carnitine levels in myocytes and cardiocytes, ONLY IN MUSCLE WILL BE EVIDENT
o Acyl-oxidations compromised, noticed in heart
o Dietary supplements raise carnintine levels which forces carnitine into cells in a non-specific manner!!!

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 Systemic carnitine defiency

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• Defect in A DIFFERENT transporter located in liver, CNS, muscle isoform
o Hepatomegaly- TAGS synthesized here cannot be exported to mitochondria for tag oxidation.• Reduced carnitine levels in several tissues
• More responsive to carnitine therapy

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o Secondary carnitine deficiencies

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 Metabolic disorders

• Disorders in FAO, ETC, drugs causing adverse effects on carnitine metabolism
• Not inheritable like primary
• Restriction of strenuous activity and snacking regularly on carb rich food to avoid fat degradation energy requirements and prevent hypoglycemia from developing

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steps of Beta Fatty acid oxidation

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o Oxidation producing FADH2
o Hydration
o Oxidation producing NADH2
o Thiolysis releasing Acetyl CoA

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energetics of B-FAO

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At completion of cycle you would have made a net total of 129 ATP…with 2 being used for avtication step (was 131 then)

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Acetyl Dehydrogenases

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first step of FAO

- There are four fatty acyl CoA dehydrogenases, each with a specificity for either :
o LCFA, MCFA, SCFA

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Medium Chain Fatty Acyl-CoA Dehydrogenase Deficiency (MCAD)

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- Most common form of genetic defect in lipid disorder
- Autosomal recessive disorder
- Only partial production of energy because
- Decreased ability to oxidize fatty acids with 6-10 carbons
- Severe hypoglycema bc tissues increase reliance on glucose but no energy there to utilize gluconeogenesis
- MCFA detected in the urine
- Hepatomegaly
- 10% of SIDS cases linked with this
- Tx: avoid fasting
o SCFA and LCFA dehydrogenase deficiencies have also been reported and have similar symptoms

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Jamaican Vomiting Sickness (TOXINS)

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- Unripe fruit of akee tree with rare amino acid hypoglycin
- Hypoglycin metabolism produced MCPA-CoA
- MCPA-CoA is IRREVERSIBLE INHIBITOR of SCFA and LCFA dehydrogenases
- Hypoglycemia bc glucose major energy source
- Vomiting, convulsions, metabolic coma

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ODD-CHAIN fatty acid oxidation

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PropionylCoA to Succynil CoA to TCA
first step requires biotin (carboxylase)
3rd step requires B12

SuccinylCoA, a TCA intermediate
- PropionylCoAD-methylmalonyl CoALmethylmalonylCoASuccinyl CoATCA
heart cannot do this

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Deficiency in B12->

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high concentrations of methylmalonyl CoA in the blood, not breaking down odd chain fatty acids

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PEROXISOMAL OXIDATION: ALPHA

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o Shortening one carbon at a time to oxidize BRANCHED CHAIN fatty acids

o phytolphytanic acidprisantic acidprisantoyl-CoA--will go to regular
Boxidation

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o Refsum’s Disease

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 Phytanic acid storage syndrome in alpha oxidation of peroxisomes
 Cannot metabolize phytanic acid
 Accumulates in tissues and blood, alpha hydroxylase disorder
 Demyleniation of peripheral nerve cells
 Avoidance of chlorophyll containing foods, green leafs, meat
 Condition improves with improved diet!!!, no phytol in diet!!

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perxosimal oxidation: BETA

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o VERY LCFAMCFAmitochondria
o Initial step requires acyl-coa dehydrogenase with FAD dependent acyl-CoA oxidase
o makes acetyl CoA for reactions during energy rich states when Boxidation is inhibited

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o Zelwegger’s

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 Synthesis of peroxisomes themselves is impaired
 Cannot breakdown VLCFA or LFCA
 cannot produce pyroxine in peroxisome membranes

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Ketone Bodies...why?

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- usually the acetyl-CoA that is produced in FAOxid is combined with OAA and via citrate synthase makes CITRATE
- however, during periods of HIGH LIPID INTAKE AND LOW CARB INGESTION, the acetyl CoA supply exceeds that of the number of OAA available
- ACETYL-COA>>OAA
blood flooded with NEFAS during fasting...all want OAA, but body is using OAA in gluconeogenesis

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where KB made? where itlized?

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made in the liver, but NOT used here, no thiophorase
utilized by extrahepatic tissues...these tissues convert KB to acetyl CoA and use it themselves for TCA and energy production

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KB

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acetone, acetoacetate, B-hydroxybuturate

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DIABETES 1

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pathological ketosis

o LOW INSULIN, stimulation of HSL= lipolysis
o High ketone bodies in urine and blood
o Low pH
o Glycosuria
o Hyperglycemia b/c of high gluconeogenesis
o Osmotin diuresis
o Dehydration

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STARVATION- Ketosis

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physiological ketosis

- Glucagon>insulin
- Gluconeogenesis, takes OAA in the liver
- KB synthesis in the liver but NOT to the degree of uncontrolled type 1 diabetes

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where does Fatty acid synthesis occur?

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main site is in the liver, but can occur in brain, kidney, mammary glands, intestines, adipose tissue
occurs in the CYTOSOL...acetyl CoA must therefore be transfoered from the mitochondria to the cytosol...done so via Citrate

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When does FAS take place?

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fed state, when you have eaten and there is a release of insulin

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main enzymes of FAS

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ACCase: acetyl CoA--> malnoyl CoA
and FAS: malonyl CoA-->palmitic acid (C16:0)

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ATP citrate Lyase

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in transfering acetyl coA across the mitochondrial membrane, Citrate is converted back to actetyl CoA and OAA by this enzyme

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malic enzyme

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converts malate to pyruvate and releases NADH FAS reductions

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How does ACC make acetyle CoA--> malonyl CoA?

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this enzyme is active when it is a polymer
will use a biotin unit to first carboxylate biotin, then use BCCP-CO2 and acetyl CoA to form malonyl-CoA and BCCP
with help of BCCP, ATP, CO2, carboxylated acetyl CoA-->malonyl CoA and BCCP

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regulation of ACC

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ST:allosteric activation by citrate
allosteric inhibition by LCFA
LT: prolonged high carb.excess calories will increase ACC synthase...body is always making and storing FAS

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FAS

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malnoyl CoA-->palmitic acid
condensation, reduction, dehydration, 2nd reduction
all with ACP reductases

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sources of NADPH

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malic enzyme: malate-->pyruvate after acetylCoA/citrate has been transfered to the cytrosol from the mitochondria

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malnolyl coA and carnitine

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malonyl CoA will inhibit carnitine, carnitine is active during fatty acid oxidation
malonyl coA is active during fatty acid synthesis...why would both of them be active at the same time? malonyl shuts off carnitine so when a fatty acid is made is not degraded right away

Front 42

elongation

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addition of 2C units of malonyl CoA and NADP for electrons
occurs in the microsomal SER
the mitochondrial pathway uses acetyl CoA

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desaturation

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occurs via desatureases in the SER
humans cannot introduce double bonds from carbon 10 to the w-end of the chain
reason why we cant make EFAs and why they are required in our diet

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EFAs

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linoleic acid ((18:2; 9,12)
a-linolenic acid (18:3; 9,12,15)

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EFAs function in

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membrane structure
membrane interaction
eicasanoid synthesis
precursors for neuroproteins, myelin

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one carbon carriers and what they donate

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- THF- methyl, formyl, methylene, second two primarily for DNA synthesis-purines and pyrimidines
- B12(methylcobalamin)
- SAM

Front 47

dihydroptereote synthetase

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synthesis THF in bacteria
inhibited by sulphonamides, methotrexoate, trimethoprim

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THF

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active form of folic acid
- Donor of formyl, methylene, methyl
o Once converted to methyl-THF- is stored form…need reaction of homocysteinemethionine to reconvert back to THF…with the help of B12
o Formyl and methylene are primarily used for purine and pyrimidine synthesis
 Without THF, no DNA synthesis, no mitosis, megaloblastic anemia

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THF deficiency diagnosis

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high FIGLU in urine because not onverting it to glutamate

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THF vitamin Folic Acid

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- Involved in DNA synthesis
- Thymidilate
o Synthesis of this requires FOLIC ACID
o This is needed for DNA synthesis

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Folic Acid Deficiency

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o Dietary- no greans
o Impaired absorption or increased requirement
o can happen from anti-cancer drugs because these stop replication and act to stop THF conversion
o Megaloblastic anemia
 Macrocytes in blood smears and begaloblasts in bone marrow
 No DNA synthesis, no mitosis, no size of precursor cells
o NEURAL TUBE DEFECTS- spina bifida, anencephaly
Great help with folic acid supplementation
- Must treat with both B12 AND FOLIC ACID until you can pinpoint which is the TRUE deficiency

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Methylcobalamin (B12): 2 rxns

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needed for two reactions:
- methylmanoyl CoA to succinyl CoA in odd numbered FAO…via methylmalonyl mutase
- remethylation of homocysteine to methionine to take off the methyl group from methl-THF and to release it back to the pool
- releaseing from storage form of THF and makes available for all other reactions

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methyl trap

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methyl-THF becomes stuck in storage formfunction folate deficiency

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methyl trap

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- NOT FUNCTIONING methionine synthase/homocysteine methyltransferase
- can be due to deficiency in vitamin b12 because nothing to convert it back to THF
- THF is stuck in this form and the synthesis of purines and pyrimidines is compromised
- No DNA synthesis=no mitosis=no precursor cells=megaloblastic anemia

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Diagnosis of B12 deficiency

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- High methyl malonate in urine, no conversion to succinyl CoA

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Vitamin B12 (as vitamin)

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- is synthesized by microorganisms and needed in diet with MEATS
- Vegetarian diets are not a good source of B12
- Only water soluble vitamin to be stored
- Converts m-THF to active folate needed for DNA synthesis

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vitamin b12 Absorption

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- Parietal cells in the stomach secrete intrinsic factor(IF) this will bind to vitamin B12 in the duodenum and complex will go to the ileum for absorption

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Pernicious Anemia

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- Lack of production of IF
- Macrocytic anemia (reversible)
- No B12, no conversion of methyl-THF to THF
- No DNA synthesis
- Neurological symptoms(irreversible)
- This disease is not progressive and neurological symptoms can come first
- Reasons for deficiency
o Inadequate in diet
o No IF
o After gastrectomy so no parietal cells produced
o Pregnancy INCREASES demand
- Treatment
o High dose of B12 orally
o Intramuscular injections of cobalamin B12

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SAM: S adenosyl methionine

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- Upon methylation reactions (look in hand written notes) is converted to SAH(homocysteine)
o Must be removed from this form homocysteine because HIGH LEVELS OF HOMOCYSTEINE are DANGEROUS…need to be removed because can cause premature cardiovascular disease

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fate of Homocysteine

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o Conversion to cysteine
 Homocystinecystothianinecysteine
• Needs PLP
o Homocysteine metabolism requires folate, B12, vitamin B6

or to methionine via methionine synthase

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Hyperhomocysteinamia

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- High levels of homocysteine
- Inflammation
- Endothelial dysfunction
- Neurological manifestations

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Homocystinuria

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- Inherited disorder, autosomal recessive
- Defect in CYSTATHIONE SYNTHASE
- High premature vascular disease
- Neurological features
- Thin, long extremeties, mimic Marfan’s syndrome

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Pyridoxine

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precursor in tons of reactionsPLP
- Acts to transamination, carboxylation, deamination
- Deficiency is uncommon because this is in tonsss of food
- Secondary deficiency

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 Isoniazid

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o Drugs that are pyridoxine antagonists
when prescribing pyridoxine, but give PLP supplements

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pyridoxine needed for

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o ALA SYNTHASE
o Homocysteinecystathionecysteine
 Needed for cystathione synthase
 Can results in accumulation of homocysteine- oxidative damage, inflammation, vascular disease, etc…

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- Pyridoxine Deficiency

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o Microcytic anemia because in step of ALA synthase so proper HEME is NOT MADE…RBCs have no heme and are SMALL
o High levels of homocysteine- atherosclerosis, cardiac disease
o Peripheral neuropathy
o Seizures

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porphyrins

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- Porphyrins are cyclic compounds that are formed by the linkage of 4 pyrrole rings(tetrapyrrole) joined with methynyl bridges
- Porphyrins vary in the nature of their side chains that are attached to each pyrrole ring
- Uroporphyrin III with the acetate and proprionate side chains is the only one with assymetic side chains and is the only one that is significant to humans

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 LEAD POISONING

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ALA dehydratase- accumulation of ALA
Ferracheletase- accumulation of PG9

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porphyrias

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- Conditions and rare disorders that are caused when the enzymes in the heme synthesis pathway are not functioning properly! This leads to accumulation and EXCRETION in urine of prophryins and porphyrin precursors
- This condition may be characterized by a purple color due to pigment like porphyrins in the urine
- These conditions are usually inherited and are almost always autosomal dominant except for congenital erythropoetic porphyria which is autosomal recessive

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classification of porphyrias

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- Can be hepatic or erythropoeitic depending on where the intermediates arise
- In the hepatic, it can be either acute or chronic

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clinical features of porphyrias

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if tetrapyrrole ring not yet made-GI/neurovascular
If tetrapyrolle ring made-photosynthesis

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Acute Intermittent Porphyria

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HMB synthase
o 4 PBG  HMB (not occurring)
o GI problems and neuropsychiatric problems
increased ALA and PBG in urine
treated with HEMIN to stop ALAS synthase and accumulation of ALA

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Porphyrea Cutanea Tarda

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- This is the most common porphyria
- It is inherited and autosomal dominant
- Deficient UROPORPHYRIN DECARBOXYLASE
o Uroporphyrinogen IIICoproporphyrinogen III (NOT OCCURING)
photosensitive, skin blistering

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pathway of heme

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HEMEBILIRUBINGLUCURONIC ACID CONJUGATIONBILE

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Prehepatic Jaundice

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before reaching urine-excess breakdown of RBCs
- Excessive production of bilirubin due to excessive breakdown of RBCs
- MORE bilirubin is produced than can be conjugated in the liver
- Unconjugated bilirubin in the blood plasma INCREASES
- HIGH urobilinogen enters the enterohepatic circulation and is excreted in the urine

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Hepatic Jaundice

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NO CONJUGATION
- Damage to liver cells- maybe from hepatitis? Hepatocellular carcinoma? These liver cells themselves are INCAPABLE of conjugating the bilirubin so that it can be secreted to the bile
- Decrease in the number of functional hepatocytes, decrease in the amount of bilirubin conjugated
- Unconjugated bilirubin leaks into the blood->LEVELS OF UNCONJUGATED BILIRUBIN INCREASE!!!
- UROBILIN IN THE URINE INCREASES
- AST/ALT will be able to detect this as HEPATIC DAMAGE

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Post-hepatic jaundice

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CONJUGATED bilirubin accumulated
- Obstruction in the bile duct!!! So the conjugated bilirubin can get out, but cannot get to the bile!
- Biliary stones, tumors, tumors of head of pancreas
- Conjugated bilirubin to hepatic veins->blood stream-> increases levels of conjugated bilirubin in plasma
- Conjugatied bilirubin reaches the kidneys and is excreted causing DARK URINE
- Decrease in sterocobilin- pale stools
o because the bacteria that removes the glucuronide from the conjugation are not present…nothing reaches this bacteria

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Neonatal Jaundice

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- accelerated hemolysis around the time of birth, RBCs being degraded, but the liver is still immature and cannot handle this excess degradation of RBCs and associated high levels of bilirubin
- excess bilirubin bilirubin due to the breakdown of RBCs cannot be conjugated by the liver(immature)
o levels of unconjugated bilirubin INCREASE
o penetrates the BBB->goes to basal ganglia when albumin capacity is saturated
- light therapy- helps unconjugated bilirubin to still be excreted to the bile
o the blue fluorescent light makes unconjugated bilirubin more polar and soluble

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Crigler-Najjar
TYPE I

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- rare, due to a genetic mutation in a gene, there is NO BILIRUBIN GLUCURONYL TRANSFERASE
- high jaundice and unconjugated bilirubin
- FATALLLL, 12-15 months death
- Need liver transplant ASAP
- SLIGHT help with phototherapy…not really effective

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Crigler-Najjar TYPE 2

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- Some activity of the enzyme is STILL RETAINED
- Not fatal
- Phototherapy and phenobarbital is used
o Phenobarbital causes hypertrophy of the ER
 Increases the synthesis of bilirubin glucuronyl transferase enzyme

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Gilbert’s Syndrome

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- Quite common
- Obviously jaundice involved
- Mutation in bilirubin glucuronyl transferase enzyme, but is still 30% active
- Fluctuating hyperbilirubinanemia
- More common in males
- Symptoms exacerbated by stress…whether physical or mental