Biochemistry Firecracker questions

Amino Acids next Basic Sciences Biochemistry Cellular Energy

5 questions 0

The 9 essential amino acids are histidine, isoleucine, leucine, lysine, methionine,phenylalanine, threonine, t ryptophan, and valine. These amino acids cannot be synthesized in human cells and must be obtained from the diet. 

Only L-form (optical isomer) amino acids can be found in proteins.

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Mnemonic: “Help In Learning These Little Molecules Proves Truly Valuable" Help = Histidine In = Isoleucine Learning = Leucine These = Threonine Little = Lysine Molecules = Methionine Proves = Phenylalanine Truly = Tryptophan Valuable = Valine The acidic amino acids are aspartic acid and glutamic acid. They are negatively charged at physiologic pH. The basic amino acids are arginine, lysine, and histidine. Arginine is the most basic.Histidine does not have a charge at physiologic pH.

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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 charged DNA. Amino acids are divided into glucogenic amino acids and ketogenic amino acids. Glucogenic amino acids can enter the CAC as either pyruvate, α-ketoglutarate, succinyl-CoA, fumarate, or oxaloacetate and used to produce glucose. The ketogenic amino acids are degraded to acetyl-CoA or acetoacetate and used to produce fatty acids or other ketone bodies. These are not mutually exclusive. Some amino acids are considered both glucogenic and ketogenic.

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The exclusively ketogenic amino acids are leucine and lysine. The ketogenic and glucogenic amino acids are threonine, tryptophan, tyrosine,isoleucine, and phenylalanine. Note:

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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 next

Basic Sciences Biochemistry Cellular Energy

3 questions 0

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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 carboxylase to yield oxaloacetate

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Used in Citric Acid Cycle or Gluconeogenesis (first of 2 steps needed toless convert pyruvate back to PEP)

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Requires ATP 3) Transamination by alanine aminotransferase (ALT) to yield alanine

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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

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The glutamate ultimately enters the Urea Cycle → urea (nitrogen excretion) 4) Reduction by lactate dehydrogenase to yield lactate

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Consumes NADH

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Can enter the Cori cycle

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Cori Cycle next

Basic Sciences Biochemistry Cellular Energy

4 questions 0

During strenuous exercise when oxygen supply is insufficient, muscle cells must resort to anaerobic metabolism, where pyruvate is reduced by NADH to form lactate and 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 liver gluconeogenesis converts lactate into glucose. Glucose enters 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 2 ATP per glucose; gluconeogenesis in the liver consumes 6 ATPto generate one glucose from two lactate. Overall, 4 net ATP are consumed for 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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Basic Sciences Biochemistry Cellular Energy

4 questions 0

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

PDC is located in the mitochondrial matrix less The transport of pyruvate into mitochondria consumes energy, lowering the total ATPproduction of aerobic glucose metabolism The complex has 3 enzymes: E1 (pyruvate dehydrogenase), E2, and E3

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Reaction: pyruvate + NAD+ + CoA → acetyl-CoA + CO2 + NADH E1 requires, as a cofactor, thiamine pyrophosphate (TPP), a derivative of vitamin B1

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The rate limiting step of the reaction E2 requires, as cofactors, CoA and lipoic acid

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It is this step that produces acetyl-CoA (hence the need for CoA in this step) less + E3 requires, as cofactors, FAD (vitamin B2) and NAD (vitamin B3)

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less FAD oxidizes a lipoic acid intermediate back to lipoic acid so it can participate in more reactions → in the process, FAD is reduced to FADH2 → FADH2 is then used to reduce NAD+ to NADH The PDH complex is regulated directly through phosphorylation less PDH kinase and PDH phosphatase are part of the PDH complex and act on E1.

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Phosphorylation through PDH kinase inhibits E1, while dephosphorylation through PDHphosphatase activates E1 

PDH kinase is activated (which leads to inactivation of E1) by ATP, acetylCoA, andNADH PDH kinase is inhibited (which leads to activation of E1) by pyruvate PDC deficiency has two typical presentations: 1. Metabolic (lactic acidosis as pyruvate is shunted to lactate) 2. Neurological (hypotonia, poor feeding, lethargy, seizures, mental retardation)

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

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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 next

Basic Sciences Biochemistry Cellular Energy

7 questions 0

Citric Acid Cycle: central catabolic pathway used to generate energy through the oxidization of acetate (derived from carbohydrates, fats, and proteins) into CO 2 and H2O For each turn, the cycle produces 1 GTP, 3 NADH, 1 FADH2, and 2 CO2 

1 NADH → 3 ATP equivalents 1 FADH2 → 2 ATP equivalents

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However, because of the energy expenditure required to shuttle NADH and FADH to theETC, each turn through the citric acid cycle yields: 3 NADH x 2.5 → 7.5 ATP equivalent 1 FADH2 x 1.5 → 1.5 ATP equivalent 1 GTP → 1 ATP equivalent For a total of 12 potential and 10 actual ATPs The citric acid cycle (tricarboxylic acid cycle or Krebs cycle) takes place in the mitochondrial matrix Citrate synthase catalyzes the transfer of a 2-carbon acetyl group from acetylCoA tooxaloacetate, forming the 6-carbon molecule citrate  

Citrate synthase is inhibited by ATP, NADH and succinyl CoA and stimulated less by insulin Strongly exergonic step, regulatory point in the cycle

Aconitase catalyzes the isomerization of citrate into isocitrate 

less Fluoroacetate (a metabolic poison) inhibits the enzyme aconitase Isocitrate dehydrogenase catalyzes the oxidative decarboxylation of isocitrate to αketoglutarate NAD+ → NADH, 1st molecule of CO2 is released

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Key regulatory step that is stimulated by ADP (low energy state) and inhibited by ATP andNADH (high energy state) The α-ketoglutarate dehydrogenase complex converts α-ketoglutarate to succinylCoA

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NAD+ → NADH, 2nd molecule of CO2 is released less Regulatory step, regenerates a 4-carbon chain (CoA excluded) and requires many coenzymes, including vitamins B1, B2, B3, CoA, and lipoic acid

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Note: the same cofactors are required in the pyruvate dehydrogenase complex. 

α-ketoglutarate dehydrogenase is inhibited by NADH, succinyl CoA, ATP and GTP Succinyl-CoA synthetase converts succinyl-CoA to succinate and CoA

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less Substrate level phosphorylation: GDP + Pi → GTP The succinate dehydrogenase complex catalyzes oxidation of succinate to fumarate

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FAD → FADH2 less Mitochondrial fumarase converts fumarate to malate Malate dehydrogenase oxidizes malate to oxaloacetate, and the cycle can begin anew NAD+ → NADH

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Electron Transport Chain next Basic Sciences Biochemistry Cellular Energy

1 question 0

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Electron transport chain: uses NADH and 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 of ATP less The ETC (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

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Mobile electron carriers, such as cytochrome c and coenzyme Q, shuttle electrons between various enzyme complexes of the ETC Primary NADH electron transport system: malate-aspartate shuttle, which transportsNADH electrons to complex 1 in the mitochondria. Less commonly used NADH electron transport system: glycerol-3-phosphate shuttle Theoretically: 1 NADH yields 3 ATP and 1 FADH2 yields 2 ATP (because FADH2 electrons are transferred to complex II, a lower energy level than NADH) However, since NADH from glycolysis needs to be transported into the mitochondria and the mitochondrial membrane "leaks" protons, the actual yields are smaller As electrons flow through the ETC, protons (H+) are pumped into the mitochondrial inter-membrane space → this creates an electrochemical proton gradient ATP Synthase (Complex V): uses the electrochemical proton gradient created by theETC to pump protons (H+) back into the mitochondrial matrix to produce ATP from ADPand Pi Toxins that disrupt any component of the ETC disrupt the aerobic production of ATP → tissues that depend highly on aerobic respiration, such as the CNS and the heart are particularly affected less Amobarbital (known as amytal) and rotenONE bind to NADH dehydrogenase (complex 1) → directly inhibit electron transport Antimycin A binds to cytochrome c reductase (complex III) → directly inhibits electron transport

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Carbon monoxide and Cyanide bind to Cytochrome C oxidase (complex IV) → directly inhibit electron transport Oligomycin (a macrolide) inhibits ATP synthase (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 of ATP (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) next

Basic Sciences Biochemistry Cellular Energy

4 questions 0

HMP Shunt: a 2 phase pathway consisting of an oxidative (irreversible) phase andnonoxidative (reversible) phase that uses available glucose-6-phosphate to mainly produce NADPH and ribose-5-phosphate   

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Both phases occur in cytosol ATP is not used or produced!

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Key reactions: 1) Glucose-6-Phospate → Ribulose-5-Phospate + 2 NADPH *Enzyme: Glucose-6-Phosphate Dehydrogenase 2) Ribulose-5-Phosphate → → Ribose-5-Phosphate + G3P + F6P *Enzyme: Transketolase Oxidative phase: key enzyme is G6P dehydrogenase (G6PD), the rate-limiting enzyme; all steps of the oxidative phase are irreversible and are used to generate NADPH for reductive biosynthetic pathways less NADPH is used to reduce glutathione, a coenzyme for glutathione peroxidase which prevents oxidative damage by converting H2O2 → H2O. This is especially important in RBCs

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Increased in tissues that consume NADPH in 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 is transketolase (thiamine-dependent); all steps arereversible and are used to convert sugars to produce ribose-5-phosphate and intermediates for glycolysis and gluconeogensis

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

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Fructose-6-phosphate and glyceraldehyde 3-phosphate (products of the nonoxidative 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 inadequate NADPH production leading to less anti-oxidant activity of glutathione

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

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Transmitted in X-linked recessive fashion with a predominance in Asia, the Mediterranean, and Africa (disease provides protection against Plasmodium falciparum malaria)

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

Mono/Disaccharide Metabolic Disorders next

Basic Sciences Biochemistry Cellular Energy

4 questions 0

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

A deficiency in aldolase B leads to accumulation of phosphorylated fructose less → available phosphate levels drop → gluconeogenesis is blocked Symptoms: hypoglycemia, vomiting, jaundice, and cirrhosis Patients usually asymptomatic until challenged, in infancy, with fructose

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Treatment: avoid intake of fructose or sucrose (combination of glucose and fructose) Essential fructosuria: autosomal recessive, benign condition resulting from defect in hepatic fructokinase

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Fructose can not be phosphorylated, so it is unable to be sequestered in the less cell → elevated serum fructose levels → fructosuria Classic galactosemia: autosomal recessive deficiency in GALT (galactose-1phosphate uridyl transferase), which converts galactose-1-phosphate to glucose-1phosphate

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Absence of GALT leads to galactose-1-phosphate accumulation → toxic less 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

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

Treatment: galactose-free diet

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Galactokinase deficiency: autosomal recessive deficiency in galactokinase, which phosphorylates galactose to make galactose-1-phosphate less Accumulation of galactose → galactosemia → galactosuria Galactosemia → cataracts because the lens of the eye contains aldose 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 in tissues 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 is no sorbitol accumulation) Glucose → sorbitol (via aldose reductase) → fructose via (sorbitol dehydrogenase)

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

Phenylalanine & Tyrosine Metabolism next

Basic Sciences Biochemistry Cellular Energy

6 questions 0

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

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

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Tyrosine is a precursor for many catecholamines, neurotransmitters, melanin and thyroid hormones Phenylketonuria (PKU): autosomal recessive defects in the enzyme phenylalanine hydroxylase (PAH)

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Phenylalanine accumulates and leads to the following symptoms: - neurologic defects (e.g. seizures and mental retardation) - albinism (tyrosine required for melanin synthesis)

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- "musty odor" to their sweat & urine (due to accumulated phenylalanine conversion to phenylketones) Screened for on the 2nd or 3rd day 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) Maternal PKU: lack of proper dietary treatment in a pregnant woman with PKU → infant born with microcephaly, congenital heart defects, mental and growth retardation Malignant PKU: autosomal recessive defects in the enzyme dihydrobiopterin reductase (called malignant because restricting phenylalanine does not correct neurological problems)  Note: in malignant PKU, BH2 is not converted back to BH4 because of a defect in dihydrobiopterin reductase so DOPA needs to be supplemented in these patients Tyrosine hydroxylase: enzyme that converts Tyrosine to Di-hydrOxy-PhenylAlanine (orDOPA)

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(BH4) is a necessary co-factor for the enzyme tyrosine hydroxylase. (BH4)less is also a co-factor for phenylalanine hydroxylase. Tyrosinase: similar to tyrosine hydroxylase in that it converts Tyrosine to DOPA, but this enzyme has further catalytic activity that results in the production of melanin from DOPA

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Autosomal recessive defects in tyrosinase or albinism: absence of melanin less 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

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

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Congenital deficiency of HGD (or alkaptonuria), autosomal recessive disease with the following symptoms:

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- ↑ 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) next

Basic Sciences Biochemistry Cellular Energy

1 question 0

Branched chain ketoaciduria (maple syrup urine disease): autosomal recessive defect in the branched-chain α-ketoacid dehydrogenase complex (BCKD) 

The BCKD complex catalyzes the breakdown of Isoleucine, Leucine, and Valine

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Mnemonic: I Love Vermont maple syrup from trees with branches     

Defective BCKD → 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 next

Basic Sciences Biochemistry Cellular Energy

1 question 0

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

Lipoprotein complexes include: chylomicrons, VLDL, IDL, LDL, and HDL less Apolipoproteins are proteins that bind to lipids; they have various functions: less ApoA-I activates LCAT

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ApoB-100 is the sole protein component of LDL ApoB-48 lacks the LDL-receptor binding sequence that ApoB-100 has. It is a component of chylomicrons. ApoC-II activates lipoprotein lipase (LPL) in capillaries ApoE mediates chylomicron and IDL uptake in the liver.

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Glucose Transport next

Basic Sciences Biochemistry Cellular Energy

5 questions 0

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All GLUT transporters work via facilitated diffusion GLUT1: most cell types including RBCs and brain GLUT2 (bidirectional): pancreatic β islet cells, liver, renal tubular cells, small intestine less Low affinity and high capacity isoform – liver needs to be glycogen/glucose reservoir, but shouldn’t compete with other tissues This should look similar to glucokinase (low affinity or ↑ K m and 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)

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

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Ketones next Basic Sciences Biochemistry Cellular Energy

3 questions 0

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

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Most other tissues can use fatty acids, but brain cannot. The liver lacks theless 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 is HMG-CoA synthase.

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

If the ketone is β-hydroxybutyrate, it is converted back to acetoacetate, then less → → 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 the TCA cycle → acetyl CoA is shunted into ketogenesis)

Methylmalonic and Propionic Acidemia next Basic Sciences Biochemistry Cellular Energy

3 questions 0

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Methylmalonic acidemia and Propionic 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 B12 deficiency with 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) and carnitine supplementation (improves β-oxidation of fatty acids)

Hemoglobin (Hb) next

Basic Sciences Biochemistry Cellular Energy

6 questions 0

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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): α2β2 Hemoglobin A2 (adult): α2δ2 Hemoglobin F (fetal): α2γ2 – elevated in sickle-cell disease patients Hemoglobin’s oxygen dissociation curve is sigmoidal: the tetramer flips between 2 conformations Deoxy or T (Taut) form: low O2 affinity less Oxy or R (Relaxed) form: high (↑ 300x) O2 affinity When 2 O2 molecules 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: ↑ CO2 and/or H+ concentration stabilizes deoxygenated conformation). 4 factors cause O2 dissociation (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 O2 dissociation curve to the right – a higher O2 pressure is needed to maintain the same level of hemoglobin saturation Myoglobin has a similar structure/sequence, but is a monomer → doesn’t exhibit cooperative binding CO2 transport: CO2 is converted to H2CO3 by carbonic anhydrase less

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

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Allosteric inhibition: CO2 also binds at the hemoglobin chain N terminus, favoring the deoxy Hb form Carbon monoxide: CO is a competitive inhibitor with 200x affinity for heme compared to O2

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Carboxyhemoglobin is bright red and poisoned patients are commonly described as having a cherry-red appearance to their skin Iron in Hb is usually in the Fe2+ (ferrous), reduced state

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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 oxygendissociation curve Normally, oxidation is prevented via a reductive enzyme pathway (HMP shunt) in RBCs Drugs that cause methemoglobinemia: Metoclopramide, Procaine, Nitrites, Antimalarials,Sulfonamides , Dapsone.

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Can be easily remembered with mnemonic: A Methemoglobinemic Patient is Not AlwaysSomething Deadly. 

Treatment: methylene blue Cyanide poisoning: CN- preferentially binds to Fe3+ and inactivates cytochrome c oxidasein the electron transport chain → stops cellular respiration

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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

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Methemoglobinemia decreases the patient’s O2 carrying capacity, but methemoglobinemia can be managed whereas arrested cellular respiration is irreversible

SAM (S-Adenosyl Methionine) next Basic Sciences Biochemistry Cellular Energy

1 question 0

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

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Helps methylate DNA

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After donating its methyl group, SAM is hydrolyzed to homocysteine and adenosine; regeneration of methionine from homocysteine requires folate and vitamin B12

Fatty Acid Oxidation next Basic Sciences Biochemistry Cellular Energy

5 questions 0

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In the cytosol, long chain (> 14 C) free fatty acids are converted to fatty acyl-CoA by fatty acyl CoA synthetase. This step activates the fatty acid for transport into the mitochondria. Because the inner mitochondrial membrane is impermeable to CoA, the carnitine shuttle system is 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 membrane Reaction: 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.

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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.

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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 and medium and short chain fatty 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.

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

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MCADD (medium-chain acyl-CoA dehydrogenase deficiency): MCAD is a enzyme required for complete oxidation of medium length fatty acids. Deficiency → inability to oxidize fatty acids with 300 mg/dL); homozygotes = 6 1/10 (cholesterol > 700+ mg/dL)

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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 commonly familial combined hyperlipidemia, is characterized by decreased LDL receptor and increased ApoB. The mechanism is not fully elucidated. The inheritance pattern is autosomal dominant.

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less Due to decreased LDL receptor and increased ApoB, the characteristics lab findings areincreased serum LDL, VLDL, and triglycerides (