Biochemistry Firecracker questions

Amino Acids

Amino Acids

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Basic SciencesBiochemistryCellular Energy5 questions

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The 9 essential amino acids arehistidine,isoleucine,leucine,lysine,methionine,phenylalanine,threonine,tryptophan, andvaline. These amino acids cannot be synthesized in human cells and must be obtained from the diet.

less OnlyL-form(optical isomer) amino acids can be found in proteins.

Mnemonic: HelpInLearningTheseLittleMoleculesProvesTrulyValuable"

Help =HistidineIn =IsoleucineLearning =LeucineThese =ThreonineLittle =LysineMolecules =MethionineProves =PhenylalanineTruly =TryptophanValuable =Valine

The acidic amino acids areaspartic acidandglutamic acid. They are negatively charged at physiologic pH.

The basic amino acids are arginine,lysine, and histidine.Arginineis the most basic.Histidinedoes not have a charge at physiologic pH.

less Found in high concentrations in proteins that need to bind strongly to negative substrates. For instance, arginine and lysine are over-expressed in histones because the histones need to bind negatively chargedDNA.

Amino acids are divided intoglucogenicamino acids andketogenicamino acids. Glucogenic amino acids can enter theCACas either pyruvate, -ketoglutarate, succinyl-CoA, fumarate, or oxaloacetate and used to produceglucose. The ketogenic amino acids are degraded to acetyl-CoA or acetoacetate and used to producefatty acidsor other ketone bodies. These are not mutually exclusive. Some amino acids are considered bothglucogenic and ketogenic.

less The exclusively ketogenic amino acids areleucineandlysine.

The ketogenic and glucogenic amino acids arethreonine,tryptophan,tyrosine,isoleucine, andphenylalanine. Note: Threonine is converted to glycine and acetyl-CoA via threonine dehydrogenase. However, some texts do not consider it a ketogenic amino acid.

The exclusively glucogenic amino acids are alanine, arginine, asparagine, aspartic acid, cysteine, histidine, glutamine, glutamic acid, glycine, serine, methionine, proline, and valine.

Pyruvate Reactions



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Pyruvate can undergo 1 of 4 reactions:

1) Dehydrogenation by the Pyruvate Dehydrogenase Complex to yield acetyl-CoA

less Acetyl CoA enters the Citric Acid Cycle

2)Carboxylation by pyruvate carboxylaseto yield oxaloacetate

less Used inCitric Acid CycleorGluconeogenesis(first of 2 steps needed to convert pyruvate back toPEP)

RequiresATP3)Transamination by alanine aminotransferase (ALT)to yield alanine

less Tissues (e.g. muscle) that use amino acids for fuel generate glutamate

Glutamate can donate its amino group to pyruvate, yielding alanine

Alanine is transported to the liver, which then regenerates pyruvate and glutamate

The pyruvate undergoes Gluconeogenesis and is sent out to the body

The glutamate ultimately enters theUrea Cycle urea (nitrogen excretion)

4)Reduction by lactate dehydrogenaseto yield lactate

less ConsumesNADH Can enter the Cori cycle

Cori Cycle



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During strenuous exercise when oxygen supply is insufficient, muscle cells must resort to anaerobic metabolism, where pyruvate is reduced byNADHto formlactateand regenerateNAD+, instead of entering the Tricarboxylic Acid (TCA) Cycle.Lactate dehydrogenase(LDH) is the enzyme responsible for the reaction.

The lactate produced in the muscle cells during anaerobic metabolism enters the bloodstream and is taken up by the liver. In the livergluconeogenesisconverts lactate into glucose.Glucoseenters the bloodstream and is used by muscle cells, restarting the cycle.

In the Cori cycle lactate is produced in the muscle cells and converted to glucose in the liver, so the muscle cells can make more lactate. Glycolysis and anaerobic metabolism in themuscle cells generate 2ATPper glucose; gluconeogenesis in theliver consumes 6ATPto generate one glucose from two lactate.Overall, 4 netATPare consumedfor each round of the Cori cycle; therefore, there is a metabolic shift to the liver.

Red blood cells, which lack mitochondria, produce lactate and hence participate in the Cori cycle.

Pyruvate Dehydrogenase Complex (PDC)



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ThePyruvate Dehydrogenase Complex (PDC): converts pyruvate into acetyl-CoA through several reactions, linking glycolysis (cytoplasm) and the citric acid cycle (mitochondria)

less PDCis located inthe mitochondrial matrix The transport of pyruvate into mitochondria consumes energy, lowering the totalATPproduction of aerobic glucose metabolism

The complex has 3 enzymes: E1 (pyruvate dehydrogenase), E2, and E3

Reaction: pyruvate +NAD++ CoA acetyl-CoA + CO2+NADHE1 requires, as a cofactor,thiamine pyrophosphate (TPP), a derivative ofvitamin B1less The rate limiting step of the reaction

E2 requires, as cofactors,CoAandlipoic acidless It is this step that produces acetyl-CoA (hence the need for CoA in this step)

E3 requires, as cofactors,FAD(vitamin B2) andNAD+(vitamin B3)

less FADoxidizes a lipoic acid intermediate back to lipoic acid so it can participate in more reactions in the process,FADis reduced toFADH2FADH2is then used to reduce NAD+ toNADHThePDHcomplex is regulated directly through phosphorylation

less PDHkinase andPDHphosphatase are part of thePDHcomplex and act on E1.

Phosphorylation throughPDHkinase inhibits E1, while dephosphorylation throughPDHphosphatase activates E1

PDHkinase isactivated(which leads toinactivationof E1) byATP, acetyl-CoA, andNADHPDHkinase isinhibited(which leads toactivationof E1) bypyruvatePDCdeficiency has two typical presentations:

1. Metabolic (lactic acidosis as pyruvate is shunted to lactate)2. Neurological (hypotonia, poor feeding, lethargy, seizures, mental retardation)

less Most common form is caused by mutations in the X-linked E1 gene

Even though the E1 mutation is X-linked, it still affects females due to critical role of the enzyme in the nervous system considered X-linked dominant

Key feature: gray matter degeneration with brainstem necrosis and capillary proliferation

Treatment: very few forms respond to cofactor supplementation with thiamine

Ketogenic diets (high fat, low carbohydrate, adequate protein) have minimal success

Citric Acid Cycle



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Citric Acid Cycle: central catabolic pathway used to generate energy through the oxidization of acetate (derived from carbohydrates, fats, and proteins) into CO2and H2O

For each turn, the cycle produces 1GTP, 3NADH, 1FADH2, and 2 CO2less 1NADH 3ATPequivalents1FADH2 2ATPequivalents

However, because of the energy expenditure required to shuttleNADHandFADHto theETC, each turn through the citric acid cycle yields:

3NADHx 2.5 7.5ATPequivalent1FADH2x 1.5 1.5ATPequivalent

1GTP 1ATPequivalent

For a total of12 potentialand10 actualATPs

The citric acid cycle (tricarboxylic acid cycle or Krebs cycle)takes place in the mitochondrial matrixCitrate synthasecatalyzes the transfer of a 2-carbon acetyl group fromacetyl-CoAtooxaloacetate, forming the 6-carbon moleculecitrateless Citrate synthaseis inhibited byATP,NADHand succinyl CoA and stimulated by insulin

Strongly exergonic step, regulatory point in the cycle

Aconitasecatalyzes the isomerization of citrate intoisocitrateless Fluoroacetate (a metabolic poison) inhibits the enzymeaconitaseIsocitrate dehydrogenasecatalyzes the oxidative decarboxylation of isocitrate to-ketoglutarateless NAD+ NADH, 1stmolecule of CO2is released

Key regulatory step that is stimulated byADP(low energy state) and inhibited byATPandNADH(high energy state)

The-ketoglutarate dehydrogenasecomplex converts -ketoglutarate tosuccinyl-CoAless NAD+ NADH, 2ndmolecule of CO2is released

Regulatory step, regenerates a 4-carbon chain (CoA excluded) and requires many coenzymes, including vitamins B1, B2, B3, CoA, and lipoic acid

Note: the same cofactors are required in thepyruvate dehydrogenase complex.

-ketoglutarate dehydrogenaseis inhibited byNADH, succinyl CoA,ATPandGTPSuccinyl-CoA synthetaseconverts succinyl-CoA tosuccinateand CoA

less Substrate level phosphorylation:GDP+ PiGTPThesuccinate dehydrogenasecomplex catalyzes oxidation of succinate tofumarateless FADFADH2Mitochondrialfumaraseconverts fumarate tomalateMalate dehydrogenaseoxidizes malate tooxaloacetate, and the cycle can begin anew

less NAD+ NADHElectron Transport Chain


Basic SciencesBiochemistryCellular Energy1 question

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Electron transport chain: usesNADHand FADH2 electrons (from glycolysis, pyruvate dehydrogenase complex, and the citric acid cycle) to form a proton gradient, coupled to oxidative phosphorylation, that drives the production ofATPless TheETC(electron transport chain) is composed of 5 multi-enzyme complexes, numbered I-V, that accept and donate electrons while molecular oxygen, O2, is the final electron acceptor

Mobile electron carriers, such as cytochrome c and coenzyme Q, shuttle electrons between various enzyme complexes of theETC PrimaryNADHelectron transport system:malate-aspartate shuttle, which transportsNADHelectrons to complex 1 in the mitochondria.

Less commonly usedNADHelectron transport system: glycerol-3-phosphate shuttle

Theoretically: 1NADHyields 3ATPand 1 FADH2 yields 2ATP(because FADH2 electrons are transferred to complex II, a lower energy level thanNADH)

However, sinceNADHfrom glycolysis needs to be transported into the mitochondria and the mitochondrial membrane "leaks" protons, the actual yields are smaller

As electrons flow through theETC, protons (H+) are pumped into the mitochondrial inter-membrane space this creates an electrochemical proton gradient

ATPSynthase (Complex V): uses the electrochemical proton gradient created by theETCto pump protons (H+) back into the mitochondrial matrix to produceATPfromADPand Pi

Toxins that disrupt any component of theETCdisrupt the aerobic production ofATP tissues that depend highly on aerobic respiration, such as theCNSand the heart are particularly affected

less Amobarbital (known as amytal) and rotenONEbind toNADHdehydrogenase (complex1) directly inhibit electron transportAntimycin A binds to cytochrome c reductase (complexIII) directly inhibits electron transport

Carbon monoxide andCyanide bind toCytochromeCoxidase (complex IV) directly inhibit electron transport

Oligomycin (a macrolide) inhibitsATPsynthase (complex V) by blocking its proton channel

2,4-Dinitrophenol and doses of aspirin increase the permeability of the inner mitochondrial membrane proton gradient and oxygen consumption heat generated instead ofATP(explains the fever generated following toxic doses of aspirin)

Thermogenin in brown fat is an uncoupling agent that disrupts the proton gradient used to generate heat in animals

HMP Shunt (Pentose phosphate pathway)



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HMPShunt: a 2 phase pathway consisting of anoxidative (irreversible)phase andnonoxidative (reversible)phase that uses available glucose-6-phosphate to mainly produceNADPHand ribose-5-phosphate

less Both phases occur in cytosol

ATPisnotused or produced!

Key reactions:1) Glucose-6-Phospate Ribulose-5-Phospate + 2NADPH*Enzyme: Glucose-6-Phosphate Dehydrogenase2) Ribulose-5-Phosphate Ribose-5-Phosphate + G3P + F6P*Enzyme: Transketolase

Oxidative phase: key enzyme isG6P dehydrogenase (G6PD), the rate-limiting enzyme; all steps of the oxidative phase areirreversibleand are used to generateNADPHfor reductive biosynthetic pathways

less NADPHis used to reduceglutathione, a coenzyme for glutathione peroxidase which prevents oxidative damage by converting H2O2 H2O. This is especially important in RBCs

Increased in tissues that consumeNADPHin reductive pathways like adipose tissue for fatty acid synthesis, gonads and adrenal cortex for steroid synthesis, liver for fatty acid and cholesterol synthesis, and glutathione reduction inside RBCs

Nonoxidative phase: key enzyme istransketolase (thiamine-dependent); all steps arereversibleand are used to convert sugars to produce ribose-5-phosphate and intermediates for glycolysis and gluconeogensis

less Pentose sugars like ribose-5-phosphate are used for nucleotide synthesis

Fructose-6-phosphate and glyceraldehyde 3-phosphate (products of the non-oxidative phase) are used as substrates for glycolysis in fed state, and intermediates in gluconeogenesis in the fasting state

G6PD deficiency: hemolytic anemia when RBCs are exposed to oxidative stress because of inadequateNADPHproduction leading to less anti-oxidant activity of glutathione

less Causes of oxidizing stress: infections, fava beans, drugs (e.g. sulfonamides, dapsone, primaquine)

Transmitted in X-linked recessive fashion with a predominance in Asia, the Mediterranean, and Africa (disease provides protection againstPlasmodium falciparummalaria)

On a peripheral smear look forHeinz bodies(inclusions in RBCs composed of denaturedHemoglobin) anddegmacytes (bite cells)(result of splenic macrophages removing Heinz bodies)

Mono/Disaccharide Metabolic Disorders



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Hereditary fructose intolerance: autosomal recessivedeficiency of aldolase B, which cleaves fructose 1-phosphate to 3-carbon molecules.

less A deficiency in aldolase B leads to accumulation of phosphorylated fructose available phosphate levels drop gluconeogenesis is blocked

Symptoms: hypoglycemia, vomiting, jaundice, and cirrhosis

Patients usually asymptomatic until challenged, in infancy, with fructose

Treatment: avoid intake of fructose or sucrose (combination of glucose and fructose)

Essential fructosuria: autosomal recessive, benign condition resulting fromdefect in hepatic fructokinaseless Fructose can not be phosphorylated, so it is unable to be sequestered in the cell elevated serum fructose levels fructosuria

Classic galactosemia: autosomal recessive deficiency inGALT(galactose-1-phosphate uridyltransferase), which converts galactose-1-phosphate to glucose-1-phosphate

less Absence ofGALTleads to galactose-1-phosphate accumulation toxic

All states mandate neonatal screening because lactose (i.e. milk) is metabolized to glucose and galactose

Symptoms: poor growth, hepatic dysfunction (jaundice, coagulopathy, hepatomegaly), ascites, cataracts, mental retardation

These infants also have an risk for E. coli septicemia.

Treatment: galactose-free diet

Galactokinase deficiency: autosomal recessivedeficiency in galactokinase, which phosphorylates galactose to make galactose-1-phosphate

less Accumulation of galactose galactosemia galactosuria

Galactosemia cataracts because the lens of the eye containsaldose reductase, which converts galactose to galactitol, an osmotically active alcohol

Lactase deficiency: age-related or hereditary lactose intolerance due to expression of lactase (a brush-border enzyme) or transient expression following gastroenteritis

less Symptoms: osmotic diarrhea, bloating/cramps

Treatment: avoid lactose

Sorbitol accumulation: high blood levels of glucose (or fructose or galactose) lead to osmotic damage from sorbitol accumulation intissues that lack sorbitol dehydrogenase cataracts, diabetic retinopathy, and peripheral neuropathy

less Liver, ovaries, and seminal vesicles have both aldose reductase and sorbitol dehydrogenase (thus, there isno sorbitol accumulation)Glucose sorbitol (viaaldose reductase) fructose via (sorbitol dehydrogenase)

Schwann cells, lens, retina, and kidneys only have aldose reductase (thus, there is sorbitol accumulation in hyperglycemic states)

Phenylalanine & Tyrosine Metabolism



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Phenylalanine hydroxylase (PAH): enzyme that converts Phenylalanine to Tyrosine

less In this reaction, tetrahydrobiopterin (BH4), the required cofactor, is converted to dihydrobiopterin (BH2)

BH2is converted back to BH4via the enzymedihydrobiopterin reductase Tyrosine is a precursor for many catecholamines, neurotransmitters, melanin and thyroid hormones

Phenylketonuria (PKU): autosomal recessive defects in the enzyme phenylalanine hydroxylase (PAH)

less Phenylalanine accumulates and leads to the following symptoms:- neurologic defects (e.g. seizures and mental retardation)- albinism (tyrosine required for melanin synthesis)- "musty odor" to their sweat & urine (due to accumulated phenylalanine conversion to phenylketones)

Screened for on the 2ndor 3rdday of life due to presence of maternal enzyme at birth

Treatment: restrict phenylalanine and aspartame (contains phenylalanine) in diet and tyrosine intake (becomes an essential amino acid)

MaternalPKU: lack of proper dietary treatment in a pregnant woman withPKU infant born with microcephaly, congenital heart defects, mental and growth retardation

MalignantPKU: autosomal recessive defects in the enzyme dihydrobiopterin reductase (called malignant because restricting phenylalanine does not correct neurological problems)

Note: in malignantPKU, BH2isnotconverted back to BH4because of a defect in dihydrobiopterin reductase soDOPAneeds to be supplemented in these patients

Tyrosine hydroxylase: enzyme that converts Tyrosine toDi-hydrOxy-PhenylAlanine (orDOPA)

less (BH4) is a necessary co-factor for the enzyme tyrosine hydroxylase. (BH4) is also a co-factor for phenylalanine hydroxylase.

Tyrosinase: similar to tyrosine hydroxylase in that it converts Tyrosine toDOPA, but this enzyme has further catalytic activity that results in the production of melanin fromDOPAless Autosomal recessivedefects in tyrosinaseoralbinism: absence of melanin in hair (white hair), eyes (photophobia), and skin (increased risk of UV related skin cancer

Homogentisic acid dioxygenase (HGD): enzyme that is part of the degradative pathway of tyrosine into fumarate

less The catabolic process involves homogentisate (or alkapton) as an intermediate

Congenital deficiency ofHGD(oralkaptonuria), autosomal recessive disease with the following symptoms:

- homogentisate excreted in urine (if the urine is left standing it will turn black)- homogentisate also polymerizes and deposits in joints joint arthritis, ankylosis, and arthralgias (toxic to cartilage)- dark connective tissue (called ochronosis)- brown hyper-pigmented sclera

Branched-chain Ketoaciduria (Maple Syrup Urine Disease)



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Branched chain ketoaciduria (maple syrup urine disease):autosomal recessivedefect in the branched-chain -ketoacid dehydrogenase complex (BCKD)

less TheBCKDcomplex catalyzes the breakdown ofIsoleucine,Leucine, andValineMnemonic:ILoveVermontmaplesyrup from trees withbranches DefectiveBCKD accumulation of branched chain amino acids in the blood and the brain irreversible neurological damage

Symptoms typically present in the first few days of life (days 4-7) and include poor feeding, vomiting, poor weight gain, lethargy, and maple syrup odor to the urine

Isoleucine: characteristic maple syrup odor of the urine

Leucine: readily crosses the blood-brain barrier and is responsible for the neurological symptoms

Treatment: restrict amino acid intake, and a small number of patients respond to thiamine (vitamin B1) supplementation

Lipoprotein Complexes and Apolipoproteins



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Lipoprotein complexes are composed of cholesterol, TGs (triglycerides), and phospholipids and apolipoproteins.

less Lipoprotein complexes include: chylomicrons,VLDL,IDL,LDL, andHDLApolipoproteins are proteins that bind to lipids; they have various functions:

less ApoA-I activatesLCAT ApoB-100 is the sole protein component ofLDL ApoB-48 lacks theLDL-receptor binding sequence that ApoB-100 has. It is a component of chylomicrons.

ApoC-II activates lipoprotein lipase (LPL) in capillaries

ApoE mediates chylomicron andIDLuptake in the liver.

Glucose Transport



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AllGLUTtransporters work via facilitated diffusion

GLUT1: most cell types including RBCs and brain

GLUT2 (bidirectional): pancreatic islet cells, liver, renal tubular cells, small intestine

less Low affinity and high capacity isoform liver needs to be glycogen/glucose reservoir, but shouldnt compete with other tissuesThis should look similar to glucokinase (low affinity or Kmand high capacity or Vmax) because it has a similar tissue distribution

GLUT3: neurons, testes, and the placenta

GLUT4: adipose tissue and striated muscle (skeletal and cardiac)

less Insulin regulates insertion of GLUT4 transporters into cell membrane in response to high glucose levels

Ketones



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Acetoacetate, -hydroxybutyrate, and acetone are the ketones produced during ketogenesis: Produced by liver for use in thebrainand heart.

less Most other tissues can use fatty acids, but brain cannot. The liver lacks the enzymes to use ketones

During hypoglycemia, fatty acids are sent to the liver for oxidation acetyl-CoA levels.

less The rate limiting enzyme in the formation of ketones isHMG-CoA synthase.

Ketone utilization: If the ketone is acetoacetate, this is converted (via multiple steps) to 2 acetyl-CoA molecules that enter theTCAcycle

less If the ketone is -hydroxybutyrate, it is converted back to acetoacetate, then 2 acetyl-CoA

Ketones are excreted in urine. Acetone, from spontaneous decarboxylation of acetoacetate, causes the "fruity odor" detected on breath during ketoacidosis

Diabetic ketoacidosis: insulin (mostly in Type I diabetes) leads to ketone production because cells are unable to utilize serum glucose without insulin ( glucose in cells oxaloacetate is shunted into gluconeogenesis stops theTCAcycle acetyl CoA is shunted into ketogenesis)

Methylmalonic and Propionic Acidemia



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Methylmalonic acidemiaandPropionic acidemia: autosomal recessive disorders of enzymes in the pathway that converts propionyl CoA to succinyl CoA (process that produces energy or glucose from odd-chain fatty acids or certain amino acids)

less Pathway: propionyl CoA methylmalonyl CoA succinyl CoA

Propionyl CoA carboxylase: enzyme that catalyzes the conversion of proprionyl CoA to methylmalonyl CoA (deficiency of this enzyme leads to propionic acidemia)

Methylmalonyl CoA mutase: enzyme that catalyzes the conversion of methylmalonyl CoA to succinyl CoA, requiring vitamin B12 as a cofactor (deficiency of this enzyme leads to methylmalonic acidemia)

Symptoms of both include: ketosis, metabolic acidosis, vomiting, lethargy, poor feeding, neutropenia, and developmental/neurological complications

Propionic acidemia levels of propionic acid in the blood

Methylmalonic acidemia levels of propionic acid and levels of methylmalonic acid in the blood

Need to rule out vitamin B12deficiencywith methylmalonic acidemia because some neurologic symptoms are reversible

Treatment for both:low-protein diet(specifically intake of methionine, valine, threonine, isoleucine, and odd-chain fatty acids because they are all broken down into propionyl CoA) andcarnitine supplementation(improves -oxidation of fatty acids)

Hemoglobin (Hb)



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Tetramer (4 subunits); each subunit polypeptide has a heme molecule at its center and each heme molecule can carry 1 oxygen molecule

less Hemoglobin A (adult): 22 Hemoglobin A2 (adult): 22 Hemoglobin F (fetal): 22 elevated in sickle-cell disease patients

Hemoglobins oxygen dissociation curve is sigmoidal: the tetramer flips between 2 conformations

less Deoxy orT(Taut) form:lowO2affinity

Oxy orR(Relaxed) form:high( 300x) O2affinity

When 2 O2molecules are bound to the T form, conformation switches to R and all 4 sites can be filled

The T to R shift occurs under conditions of high oxygen tension (i.e. the lungs) and the R to T shift occurs under conditions of low oxygen tension.

Lung: High O2 oxygenated Hb.Tissues: Low O2 deoxygenated Hb (Bohr effect: CO2and/or H+concentration stabilizes deoxygenated conformation).

4 factors cause O2dissociation (T form favored):

less 1) pH: relative acidic environment, like peripheral tissues

2) CO2: produced by cellular metabolism

3) 2,3-DPG(diphosphoglycerate, the same as bisphosphoglycerate): stabilizes the T conformation, produced by glycolysis

4) temperature

These factors shift the O2dissociation curve to theright a higher O2pressure is needed to maintain the same level of hemoglobin saturation

Myoglobin has a similar structure/sequence, but is amonomer doesnt exhibit cooperative binding

CO2transport: CO2is converted to H2CO3bycarbonic anhydraseless H2CO3(carbonic acid) dissociates to bicarbonate and a proton; the H+binds to hemoglobin and thus has no effect on serum pH

Allosteric inhibition: CO2also binds at the hemoglobin chain N terminus, favoring the deoxy Hb form

Carbon monoxide: CO is acompetitive inhibitor with 200x affinityfor heme compared to O2less Carboxyhemoglobin is bright red and poisoned patients are commonly described as having acherry-red appearance to their skinIron in Hb is usually in the Fe2+(ferrous), reduced state

less Methemoglobinemia: oxidation to the Fe3+(ferric) state leads to decreased affinity of O2at these heme sites; however, at other non-oxidized heme sites, there is a compensatory increase in affinity leading to a left shift of the oxygen-dissociation curve

Normally, oxidation is prevented via a reductive enzyme pathway (HMPshunt) in RBCs

Drugs that cause methemoglobinemia:Metoclopramide,Procaine,Nitrites,Antimalarials,Sulfonamides,Dapsone.

Can be easily remembered with mnemonic: AMethemoglobinemicPatient isNotAlwaysSomethingDeadly.

Treatment: methylene blue

Cyanide poisoning: CN-preferentially binds to Fe3+andinactivates cytochrome c oxidasein the electron transport chain stops cellular respiration

less Nitrites can be used to convert Hb to methemoglobin methemoglobin then binds the CN- use sodium thiosulfate to chelate this CN-and yield thiocyanate renally excreted

Methemoglobinemia decreases the patients O2carrying capacity, but methemoglobinemia can be managed whereas arrested cellular respiration is irreversible

SAM (S-Adenosyl Methionine)



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SAM(S-Adenosyl Methionine): the primary methyl donor of the body

less Helps methylateDNA After donating its methyl group,SAMis hydrolyzed to homocysteine and adenosine; regeneration of methionine from homocysteine requires folate and vitamin B12

Fatty Acid Oxidation



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In the cytosol, long chain (> 14 C) free fatty acids are converted to fatty acyl-CoA byfatty acyl CoA synthetase. This step activates the fatty acid for transport into the mitochondria.

Because the inner mitochondrial membrane is impermeable to CoA, thecarnitine shuttle systemis required to transport the fatty acyl CoA into the mitochondrial matrix.

less Step 1:Enzyme:CAT-I (carnitine acyl transferase I) on the outer mitochondrial membraneReaction: Fatty acyl-CoA + carnitine fatty acyl carnitine + free CoA

CoA remains in the cytosol, and fatty acyl carnitine can now pass through the inner mitochondrial membrane.

Step 2:

Enzyme:CAT-II on the inner surface of the inner mitochondrial membrane

Reaction: Fatty acyl carnitine + CoA (already in the mitochondrial matrix) fatty acyl CoA + free carnitine

Fatty acyl CoA stays in the mitochondrial matrix for further metabolism, and carnitine leaves the matrix to be used again in the shuttle.

Carnitine deficiency decreased ability to utilize long chain fatty acids as a fuel source. Can be due to environmental (e.g. malnutrition) or genetic factors (e.g.CAT-I deficiency).

Symptoms: Muscle aches and fatigue following exercise, free fatty acid levels in the blood, hypoketotic hypoglycemia.

Treatment: Diet high in carbohydrates andmedium and short chainfatty acids, low in long chain fatty acids.

Malonyl-CoA, an intermediate in fatty acid biosynthesis, inhibits this shuttle system to prevent newly synthesized fatty acids from entering the degradation pathway, and thus prevent a futile synthesis-degradation cycle

Medium and short chain fatty acids directly enter the mitochondrial matrix without need for a special transport.

less In the mitochondrial matrix, fatty acyl-CoA synthetase activates short/medium chain fatty acids to fatty acyl-CoA molecules.

MCADD(medium-chain acyl-CoA dehydrogenase deficiency):MCADis a enzyme required for complete oxidation of medium length fatty acids. Deficiency inability to oxidize fatty acids with 300 mg/dL); homozygotes = 1/106(cholesterol > 700+ mg/dL)

Heterozygotes (1 in 500) have total serum cholesterol around 300 mg/dL. Homozygotes (very rare) have total serum cholesterol 700 mg/dL or greater and have poor prognosis due to myocardial infarction before age 20.

Type IIb dyslipoproteinemia, or more commonlyfamilial combined hyperlipidemia, is characterized bydecreasedLDLreceptorandincreased ApoB. The mechanism is not fully elucidated. The inheritance pattern isautosomal dominant.

less Due to decreasedLDLreceptor and increased ApoB, the characteristics lab findings areincreased serumLDL,VLDL, and triglycerides(

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