Biochem Flashcards
Osteogenesis imperfecta
Multiple fracture, blue sclerae, hearing loss, dental
Abn type I collagen
Problem in triple helix formation
Ehlers Danlos
Type I or V collagen
Problem in collagen fibrils cross linking
Alport
Progressive nephritis, deafness, ocular distubance
X linked
Type IV collagen
Elastin
Rich in proline, glycine in nonhydroxylated form
Tropolastin with fibrillin scaffolding
Cross linking extracellulalry
If mutated, Marfan (fibrillin defect)
Wrinkles of aging due to reduced collagen/elastin production
Imprinting and diseases
Both Prader Willi and Angelman’s in chromosome 15
P= paternal allele not expressed
M=maternal allele not expressed
Prader: mental retard, hyperphagia, obesity, hypogonadism hypotonia
Angelman: mental retard, seizure, ataxia, inappropriate laughter
X link dominant
Hypophosphatemic rickets:
vitamin D resistant rickets
Increased phosphate wasting at proximal tubule
Mitochondrial myopathies
Rare disorders from mutations in mitochondria
Often presents with myopathy, CNS disease
Muscle Bx= ragged red fibers
Familial hypercholesterolemia
Hyperlipidemia type IIA
AD
Elevated LDL due to defective or absent LDL receptor
Homozygote >700+ mg/dl, hetero 300 mg/dl
Hereditary hemorrhagic telangiectasia
Osler-Weber-Rendu syndrome
AD
Telangiectasia, recurrent epistaxis, skin discoloration, AVM
Hereditary spherocytosis
AD
Spectrin, ankyrin defects
Hemolytic anemia, increased MCHC, splenectomy curative
Huntington
AD
Depression, prog dementia, choreiform movement, caudate atrophy, decreased GABA and ACH
Chromosome 4 (Hunting 4 food)
Marfan
AD
Subluxation of lenses
Long extremities
aortic incompetence and dissecting aortic aneurysm, floppy mitral valve
MEN
AD
MEN2A and 2B due to ret gene
NF type 1
AD
Cafe au lait spot, neural tumor, lisch nodules (pigmented iris hamartomas)
Chromosome 17
Tuberous sclerosis
AD Facial lesions (adenoma sebaceum), hypopigmented ash leaf spots on skin, cortical and retinal hamartomas, seizures, mental retardation, renal cyst, renal angiomyolipomas, cardiac rhabdomyomas
Increased incidence of astrocytomas
Incomplete penetrance, variable presentation
VHL disease
AD
hemangioblastoma of retina, cerebellum, medulla
Major develop multiple bilateral RCC and other tumors
Constituitive expression of HIF, activation of angiogenic GF
Chromosome 3 (VHL=three letters)
Autosomal recessive
Albinism, ARPKD (formerly known as infantile, vs ADPKA=AD), CF, glycogen storage, hemochromatosis, mucopolysacchridoses (except for Hunter’s= XL), phenylketonuria, sickle, sphingolipidoses (except Fabry’s), thalassemias
X linked
Bruton’s agammaglobulinemia, Wiskott-Aldrich, Fabry’s, G6PD, Ocular albinism, Lesch-Nyhan, Duchenne’s (and Becker’s), Hemophilia A&B, Fragile X, Hunter’s, Ornithine transcarbamoylase deficiency
Be Wise, Fool’s GOLD Heed’s False HOpe.
Duchenne’s and Becker’s
X-linked frameshift
Pseudohypertrophy of calf muscle due to fibrofatty replacement of muscles, cardiac myopathy
Use of Gower’s manuver
Duchenne onset before 5 yrs, Becker’s in adolescence
Dx= muscular Bx with muscular dystrophy with increased CPK
Fragile X syndrome
X linked, affecting methylation and expression of FMR1
2nd most common cause of genetic mental retardation
Enlarged testes, long face with a large jaw, large everted ears, autism, mitral prolapse
Fragile X= eXtra large testes, jaws and ears
Trinucleotide repeat CGG
Trinucleotide repeat expansion disease
Fragile X (CGG)
Friedreich’s ataxia (GAA)
Huntington’s (CAG)
Myotonic dystrophy (CTG)
X-Girlfriend’s First Aid helped Ace my Test
Down syndrome
Flat faces, epicanthal fold, simian crease, gap between 1st two toes, duodenal atresia
Ostinum primum type ASD
Most common cause of genetic mental retardation
Results of pregnancy Quad screen
Low AFP, high bHCg, low estriol, high inhibin A
US shows high nuchal in 1st trimster translucency
Edwards’ syndrome
Election age 18,
Low set EARS, clenched hands, small jaw, prominent occiput, severe mental retardation, rocker-bottom feet, congenital heart disease.
Death within 1 yr of birth
Results of pregnancy Quad screen
Low AFP, low bHCg, low estriol, normal inhibin A
Patau’s syndrome
Puberty at 13
Small eyes, small head,
holoProsencephaly, cleft liP/Palate, Polydactylyl
Severe mental retardation, rocker-bottom feet
Results of pregnancy Quad screen
low free bHCg, low PAPP-A, high nuchal translucency
Cri-du-chat
microdeletion of short arm of Cr 5
small head, moderate to severe mental retardation, high pitched mewing, epicanthal fold, cardiac (VSD)
Williams
microdeletion of long arm of Ch 7 (deleted include elastin)
Elfin facies, intellectual diability, hypercalcemia (increase sensitivity to vitD), well developed verbal skills, extreme friendliness with strangers, CV problems
22q11
microdeletion at Ch 22q11
Cleft palate, Abnormal facies, Thymic asplasia, Cardiac defect, Hypocalcemia 2/2 parathyroid aplasia
DiGeroge=thymic, parathyroid, cardiac
Velocardiofacial=palate, facial, cardiac
Ethanol metabolism
NAD+ is the limiting agent
Zero order
Ethanol hypoglycemia: high NADH/NAD+ in liver, causing diversion of pyruvate to lactate and OAA to malate, thus inhibiting gluconeogenesis and stimulating FA synthesis.
1) Overproduction of lactate => acidosis
2) Depletion of OAA => shuts down TCA, shunting acetyl CoA into ketone production.
3) Breakdown of excess malate => increase NADPH and thus FA synthesis.
Malnutrition
Kwashiokor: protein malnutrition; skin lesion, edema, liver malfunction (fatty change due to low apolipoprotein). Small child with swollen belly
Malnutrition, Edema, Anemia, Liver (fatty)
Marasmus: energy malnutrition; tissue and muscle wasting, loss of subQ fat, and variable edema
Metabolism sites
Cytoplasm: glycolysis, FA synthesis, HMP shunt, protein/steroid/cholesterol synthesis
Mito: beta oxidation, acetyl CoA production, TCA, oxidative phosphorylation
Both: heme synthesis, urea synthesis, gluconeogenesis
(HUGs take two)
ATP production per glucose
Heart and liver: 32 via malate-asparate shuttle
Muscle: 30 via glycerol-3-phosphate shuttle
Anaerobic: 2 net ATP
Hexokinase vs. glucokinase
Hexo: ubiquitous, high affinity (low Km), low capacity (low Vmax), uninduced by insulin, inhibited by glucose-6-P
Glucokinase: liver and beta cell only, low affinity (high Km), high capacity (high Vmax), induced by insulin, inhibited by fructose-6-P
At low glucose concentration, hexokinase sequesters glucose in tissue. At high glucose concentration, excess glucose store din the liver
NADPH
Anabolic process, respiratory burst, P450, glutathione reductase.
Regulation by F2,6BP
F2,6BP is a sub product of glycolysis from F6P, that activates PKF1 (from F6P to F1,6BP) to induce more glycolysis
FBPase2 and PFK2 are part of the same complex but respond in opposite manners to phosphorylation by protein kinase A
FBPase2=> converts F2,6BP back to F6P (more gluconeogenesis)
PFK2 => converts F6P to F2,6BP (more glycolysis)
Fasting: high glucagon -> high cAMP -> high protein kinase A -> high FBPase2, low PFK-2, less glycolysis
Fed: high insulin -> low cAMP -> low protein kinase A -> low FBPase 2, high PFK2, more glycolysis
Pyruvate dehydrogenase complex
Pyruvate + NAD + CoA = Acetyl CoA, Co2, NAHD
Three enzymes with 5 cofactors:
B1, B2, B3, B5, lipoic acid
Activated by exercise: high NAD/NADH, high ADP, high Ca2+
This complex is similar to alpha ketoglutarate (same cofactors, similar substrate and action), which converts alpha ketoglutarate to succinyl CoA (TCA)
Arsenic poisoning
Inhibit lipoic acid (thus inhibit pyruvate dehydrogenase complex)
Finding: vomiting, rice water stools, garlic breath
Pyruvate dehydrogenase complex deficiency
Backup of substrates (pyruvate and alanine), resulting in lactic acidosis
Most causes due to X linked mutation for E1-alpha (subunit for PDC).
Finding: neurologic deficit, starting in infancy.
Treatment: increase intake of ketogenic nutrients
Lysine and leucine (onLy pureLy ketogenic AA)
Pyruvate metabolism
1) Alanine aminotransferase : Cahill cycle, carrying AA from muscle to liver
2) Puryvate carboxylase (biotin): OAA can replenish TCA cycle or be used in gluconeogenesis
3) Pyruvate dehydrogenase (B1,2,3,5, lipoic acid): transition from glycolysis to TCA
4) Lactic acid dehydroganse (B3): end of anerobic acid (major pathway in RBC, leukocytes, kidney medulla, lens, testes, and cornea)
TCA cycle
Products: 3NADH, 1FADH2, 2CO2, 1GTP per acetyl CoA
thus 10 ATP/acetylCoA (2x everything per glucose)
Alpha ketoglutarate dehydrogenase complex requires the same cofactors as the pyruvate dehydrogenase complex (B1,2,3,5, lipoic acid)
Citrate Is Kreb’s Starting Substrate For Making OAA.
Oxidative phosphorylation
NADH from electrons enter via malate-aspartate(cardiac/liver) and glycoerol-3-phosphate(muscle) shuttle. FADH2 transfer to complex II
1NADH -> 3ATP, 1FADH2 ->ATP
Electron transport inhibitors: rotenone, cyanide, antimycin A, CO
ATP synthase inhibitor: oligomycin
Uncoupling agent: 2,4-DNP, aspiring, thermogenin
Gluconeogenesis irreversible enzymes
Pathway Produces Fresh Glucose
1) pyruvate carboxylase (mito); pyruvate to OAA
= requires biotin, ATP, activated acetyl CoA
2) PEP carboxykinase (cyto): OAA to PEP
= requires GTP
3) F1,6BP (cyto): F1,6P to F6P
4) Glucose-6-Phosphatase (ER): glucose-6-p to glucose
Odd chain FA yield propionyl-CoA, which can enter TCA as succinyl CoA, undergoes gluconeogenesis, and serves as glucose source.
However, even chain FAT cannot produce new glucose, since they yield only acetyl-CoA equivalents.
HMP shunt (pentose phosphate pathway)
Provide a source of NADPH from an abundantly available glucose-6-phosphate.
Also yields ribose for nucleotide synthesis and glycolytic intermediates.
Two phases: oxidative vs. non oxidative, both occur in cytoplasm. No ATP produced.
Sites: lactating mammary glands, liver, adrenal cortex (site of fatty acid or steroid synthesis), RBC
Oxidative (irreversible): Glucose-6-P to 2NADPH, ribulose-5-Pi, CO2 by glucose-6-p dehydrogenase
Non oxidative (reversible): ribulose-5-P1 to ribose-5-P1, G3P, F6P by phosphopentose isomerase and transketolases (require B1)
G6PD: converts NADP+ to NADPH from G6P (becomes 6PG).
G6PD deficiency
X-linked
NADPH required to keep glutathione reduced.
Reduced NADPH in RBC leads to hemolytic anemia due to poor RBC defense against oxidizing agents
such as fava, sulfonamides, primaquines, antiTB drugs.
Infection can also precipitate hemolysis via free radical generation.
Heinz body and Bite cells
Increased malarial resistance
Essential fructosuria
AR, fructokinase deficiency (1st step).
Benign, asymptomatic, since fructose not trapped in cell
Symtpoms: fructose in blood and urine
This is milder than analogous disorders of galactose
Fructose intolerance
AR, aldolase B deficiency (2nd step).
Fructose-1-phosphate accumulates, causing a decrease in available phosphate, thus inhibiting glycogenolysis and gluconeogenesis.
Symptoms: hypoglycemia, jaundice, cirrhosis, vomiting.
Treatment: reduced intake of fructose.
Fructose bypasses RLS of glycolysis (PFK) via this pathway.
Galactokinase deficiency
AR, galactokinase deficiency (1st step) Galactitol accumulates (via aldose reductase) if galactose is present. Symptoms: relatively mild, galactose in blood and urine, infantile cataracts
May initially present as failure to tract objects or develop a social smile.
Classic galactosemia
AR, galactose-1-phosphate uridyltransferase deficiency (2nd step). (from galactose-1-p to gluclose-1-P)
Accumulation of toxic substances, galactitol.
Symptoms: FTT, jaundice, hepatomegaly, infantile cataract, mental retardation.
Treatment: exclude galactose and lactose from diet.
Fructose is to Aldolase B as Galactose is to UridylTransferase (FAB GUT)
Sorbitol
Liver, lens, ovaries, seminal vesicles have both enzymes:
Glucose to sorbitol (aldose reductase + NADPH)
Sorbitol to fructose (sorbitol dehydrogenase + NAD+)
Schwann, retina, kidney only one enzyme
Glucose to sorbitol (aldose reductase + NADPH)
Thus osmotic damage leading to cataracts, retinopathy, and peripheral neuropathy in DM.
Amino acids
Essential;
Glucogenic: met, val, his
Glucogenic/keto: ile, phe, thr, trp
Keto: leu, lys
Acidic: asp, glu (negatively charged at body pH)
Basic: arg, lys, his (arg most basic, his no charge)
Urea cycle
AA catabolism generates common metabolites (pyruvate, acetyl-CoA), which serve as metabolic fuels.
Excess nitrogen (NH4) generated is converted to urea, and excreted by the kidney
RLS: carbamoyl phosphate synthetase 1 (in cyto, the rest in mitochondria).
Carbomyol phosphate + ornithine -> citrullin -> argininosuccinate -> fumarate (out) and arginine -> urea (out) and ornithine (recycled)
AA transport by alanine and glutamate
Muscle;
AA (NH3) to alpha ketoacid, alpha ketoglutarate to glutamate (NH3)
pyruvate to alanine (NH3) (Alanine cycle, transported to liver).
pyruvate initially enters as glucose, then produces alanine and lactate, which get transported to liver (Cori cycle).
“Alan and his lactate leave the muscle”
Hyperammonemia
Excess NH4+, which depletes alpha ketoglutarate, leading to inhibtion of TCA.
Treatment: limit protein i diet. Benzoate or phenylbutyrate (which bind to AA and lead to excretion) may be given to reduced ammonia levels.
Lactulose acidify the GI tract, and trap NH4+ for excretion.
Ammonia intoxication: tremor, slurring of speech, somnolence, vomiting, cerebral edema, blurring of vision.
Ornithine transcarbamoylase deficiency
Most common urea disorder, X linked (HOpe)
Interferes with the body’s ability to eliminate ammonia, excess carbamoyl phosphate is converted to orotic acid (part of pyrimidine synthesis pathway)
Finding: increased orotic acid in blood and urine, decreased BUN, and symptoms of hyperammonemia.
Phenylketouria
AR. Decreased pheylalanine hydroxylase or decreased tetrahydrobiopterin cofactor (malignant phenylketonuria)
Tyrosine becomes ESSENTIAL.
Increased phenylalanine leads to excess phenylketones in urine. (phenylacetate, phenyllactate, phenylpyruvate).
Finding: mental retardation, growth retardation, seizures, fair skin, eczema, musty body order.
Treatment: reduce phenylalanine, increase tyrosine in diet.
Maternal PKU: microcephaly, mental retardation, growth retardation, congenital heart defects.
Alkaptonuria: ochronosis
AR. Homogentisic acid oxidase deficiency, pathway of tyrosine to fumarate. Benign disease
Finding: dark connective tissue, brown pigmented sclera, urine gets OXIDIZED and turns black on prolonged exposure.
May habe debilitating arthralgias (homogentisic acid toxic to cartilage).
Albinism
Congenital deficiency of either of the following
1) tyrosinase (can’t synthesize melanin from tyrosine)= AR
2) tyrosine transporter (decreased tyrosine so melanin)
Can result from a lack of migration of neural crest cells.
Variable inheritance due to locus heterogeneity
(vs. ocular albinism, X-linked).
Homocystinuria
Homocysteine + serine => cysthionine (cystathionine synthase/B6)
Homocysteine => methionine (homocysteine methyltransferase/B12)
Three forms. All three AR
1) Cystathionine synthase deficiency
= treat with low Met, high Cys, and high B9, B12 in diet
2) Decreased affinity of cystathionine synthase for pyridoxal phosphate
= treat with increased vitamin B6 in diet
3) Homocysteine methyltransferase (require B12)
All forms result in excess homocystine, cysteine becomes essential
Finding: high homocystein in urine, mental retardation, osteoporosis, tall stature, kyphosis, lens subluxation (downward and inward vs Marfan), and atherosclerosis (stroke/MI)
Cystinuria
AR, Renal tubular AA transporter for cysteine, ornithine, lysine and arginine in the PCT
Excess cystine in the urine can lead to precipitation of hexagonal crystals and renal staghorn calculi.
Treat with good hydration and urinary alkalinzation.
(cystine is made of two cysteines connected by disulfide)
Maple syrup urine disease
AR. Blocked degradation of branched AA (ile, leu, val)
Due to reduced alpha ketoacid dehydrogenase (B1)
Causes increased alpha ketoacid in the blood, esp leu.
Symptoms: severe CNS defects, mental retardation, death.
Urine smells like maple syrup.
I Love Vermont maple syrup from maple trees with branches.
Hartnup disease
AR, defective neutral AA transporter on renal and intestinal epithelial cells.
Causes tryptophan excretion in urine and decreased absorption from the gut.
Leads to pellagra (B3), imagine three indian guys
Glycogen regulation
Glucagon/EP induces adenylyl cyclase (up cAMP), high cAMP activates protein kinase A, which activates glycogen phosphorylase kinase, which activates glycogen phosphorylase to release glucose.
Insulin activates protein phosphatase, which inactivate both glycogen phosphorylase kinase AND glycogen phosphorylase.
Ca2+/calmodulin in muscle activates phosphorylase kinase so that glycogenolysis is coordinated with muscle activity.
Glycogen
Branches have alpha (1,6), linkages have alpha (1,4)
Skeletal: glycogen undergoes glycogenolysis -> glucose-1-phosphate -> glucose-6-phosphate, which is rapidly metabolized during exercise.
Hepatocyte: glycogen is stored and undergoes glycogenolysis to maintain blood sugar at appropriate levels.
Note: a small amount of glycogen is degraded in lysosomes by alpha 1,4 glucosidase.
Fatty acid metabolism
FA degradation occurs where its products will be consumed (in the mito).
Carnitine deficiency: inability to transport LCFA into the mitochondria, resulting in toxic accumulation.
Symptoms: weakness, hypotonia, and hypoketotic hypoglycemia.
Acyl-CoA dehydrogenase deficiency: increased dicarboxylic acid, decreased glucose and ketones.
Sytrate= SYnthesis, citrate shuttle (ATP citrate lyase produces acetyl CoA)
CARnitine=CARnage (large killing) of fatty acid, carnitine shuttle (fatty acid CoA synthetase produces acyl CoA)
Ketone bodies
In the liver, FA and AA are metabolized to acetoacetate and beta hydroxybutyrate (to be used in muscle/brain).
1) In prolonged starvation and DKA, OAA is depleted for gluconeogenesis.
2) In alcoholism, excess NADH shunts OAA to malate.
Both processes stall the TCA cycle, which shunts glucose and FFA toward the production of ketone bodies.
Made from HMG-CoA. Metabolized by the brain to molecules of acetylCoA. Excreted in the urine.
Fasting and starvation
Fed state: glycolysis and aerobic respiration
Fasting: hepatic glycogenolysis > hepatic gluconeogenesis/adipose releases FFA.
Starvation 1-3 days: hepatic glycogenolysis, adipose release of FFA, muscle and liver which shift fuel use from glucose to FFA, hepatic gluconeogeneis from peripheral tissue lactate and alanine, and from adipose tissue glycerol and propionyl CoA(only from odd chain FFA, the only triacylglycerol components that contribute to gluconeogenesis).
- Glycogen reserves depleted after day 1.
- RBC lacks mitochondria so cannot use ketones.
Starvation after 3 days: adipose stores (ketone bodies become the main source of energy for the brain and heart). After that, vital protein degradation.
*Amount of adipose stores determines survival time.
1g protein/carb =4 kcal
1g fat = 9kcal
Cholesterol synthesis
RLS is catalyzed by HMG-CoA reductase, which converts HMG-CoA to mevalonate.
2/3 of plasma cholesterol is esterified by lecithin-cholesterol acyltransferase LCAT.
Nascent HDL uses LCAT to catalyzed esterification of cholesterol, then become mature HDL.
Mature HDL uses cholesterol ester transfer protein (CETP) to mediate transfer of cholesterol esters to other lipoprotein particles.
Familial dyslipidemia
1-hyperchylomicronemia
AR,
Lipoprotein lipase deficiency or altered apolipoprotein C-II.
Cause pancreatitis, hepatosplenomegaly, and eruptive/pruritis xanthomas (no increased risk for atherosclerosis).
Increased blood level: chylomicrons, TG, cholesterol
Familial dyslipidemia
2a-familial hypercholesterolemia
AUTOSOMAL DOMINANT
Absent or reduced LDL receptors.
Causes acccelerated atherosclerosis, tendon xanthomas, and corneal arcus.
Increased blood level: LDL, cholesterol
Familial dyslipidemia
IV-hyper-triglyceridemia
AUTOSOMAL DOMINANT
Hepatic overproduction of VLDL, causes pancreatitis
Increased blood level: VLDL, TG
Abetalipoproteinemia
AR, mutation if microsomal triglyceride transfer protein (MTP) gene
Decreased B-48, B-100 => decreased chylomicron and VLDL synthesis and secretion.
Symptoms appear in the first few months of life. Intestinal Bx show lipid accumulation within enterocytes due to inability to absorbed lipid as chylomicrons.
Findings: FTT, steatorrhea, acanthocytosis, ataxia, night blindness.
Lipoprotein functions
Chylomicrons: delivers TG to peripheral tissues, delivers cholesterol to liver in the form of chylomicron remnants (mostly depleted of their triacylglycerol). Secreted by intestinal epithelial cells
VLDL: delivers dietary TG to peripheral tissue, secreted by liver.
IDL: formed in the degradation of VLDL, delivers TG and cholesterol to liver.
LDL: delivers hepatic cholesterol to peripheral tissues. Formed by hepatic lipase modifcation of IDL in the peripheral tissue. Taken up by target cells via receptor mediated endocytosis.
HDL: mediates reverse cholesterol transport from periphery to liver. Acts as a repository for apoC and apoE, which are needed for chylomicron and VLDL metabolism. Secreted from both liver and intestine..
Major apolipoproteins
E: mediates remnants reuptake: chylo, CR, VLDL, IDL, HDL
(Only LDL lacks E)
A-1: activates LCAT, only in HDL
C-II: (c for cofactor) Lipoprtein lipase cofactor: chylo, VDLD, HDL.
B-48: mediates chylo secretion: chylo and CR
B-100: binds LDL receptor: VLDL, IDL, LDL
Urea cycle
Ordinarily, careless crappers are also frivolous about urination
Ornithine + carbamonyl phosphate (by OTC) => citrullin (+aspartate) => argininosuccinate => arginine (fumarate out) => urea and ornithine
Carbamonyl phosphate synthesized by carbamoyl phosphate synthetase I with N acetyl glutamate cofactor
N acetylglutamate deficiency
Required cofactor for carbamoyl phsophate synthetase I
Absence of N acetylglutamate => hyperammonemia
Presentation identifcal to carbamoyl phosphate synthetase I deficiency.
However increased ornithine with normal urea cycle enzymes suggest hereditary N acetylglutamate deficiency.
