Biochemistry - Metabolism Flashcards

Question

Lactase deficiency * Definition * Primary * Secondary * Congenital * Diagnosis * Findings * Treatment

Answer 1

* Definition * Insufficient lactase enzyme --\> dietary lactose intolerance. * Lactase functions on the brush border to digest lactose (in human and cow milk) into glucose and galactose. * Primary * Age-dependent decline after childhood (absence of lactase-persistent allele), common in people of Asian, African, or Native American descent. * Secondary * Loss of brush border due to gastroenteritis (e.g., rotavirus), autoimmune disease, etc. * Congenital * Rare, due to defective gene. * Diagnosis * Stool demonstrates decreased pH and breath shows increased hydrogen content with lactose tolerance test. * Intestinal biopsy reveals normal mucosa in patients with hereditary lactose intolerance. * Findings * Bloating, cramps, flatulence, osmotic diarrhea. * Treatment * Avoid dairy products or add lactase pills to diet * Lactose-free milk.

Answer 2

* Form found in proteins * Only L-form amino acids are found in proteins. * Essential * All essential amino acids need to be supplied in the diet. * _Glucogenic_: methionine (Met), valine (Val), histidine (His). * _Glucogenic/ketogenic_: isoleucine (Ile), phenylalanine (Phe), threonine (Thr), tryptophan (Trp). * _Ketogenic_: leucine (Leu), lysine (Lys). * Acidic * Aspartic acid (Asp) and glutamic acid (Glu). * Negatively charged at body pH. * Basic * Arginine (Arg), lysine (Lys), histidine (His). * Arg is most basic. * His has no charge at body pH. * Arg and His are required during periods of growth. * Arg and Lys are increased in histones, which bind negatively charged DNA.

Answer 3

* Amino acid catabolism results in the formation of common metabolites (e.g., pyruvate, acetyl- CoA), which serve as metabolic fuels. * Excess nitrogen (NH3) generated by this process is converted to urea and excreted by the kidneys. * ****_O_**rdinarily, **_C_**areless **_C_**rappers **_A_**re **_A_**lso **_F_**rivolous **_A_**bout **_U_**rination.** * **_O_**rnithine * **_C_**arbamoyl phosphate * **_C_**itrulline * **_A_**spartate * **_A_**rgininosuccinate * **_F_**umarate * **_A_**rginine * **_U_**rea

Answer 4

* Definition * Can be acquired (e.g., liver disease) or hereditary (e.g., urea cycle enzyme deficiencies). * Results in excess NH4+, which depletes α-ketoglutarate, leading to inhibition of TCA cycle. * Treatment * Limit protein in diet. * Benzoate or phenylbutyrate (both of which bind amino acid and lead to excretion) may be given to decreased ammonia levels. * Lactulose to acidify the GI tract and trap NH4+ for excretion. * **Ammonia intoxication** * Tremor (asterixis), slurring of speech, somnolence, vomiting, cerebral edema, blurring of vision.

Answer 5

* Required cofactor for carbamoyl phosphate synthetase I. * Absence of N-acetylglutamate --\> hyperammonemia. * Presentation is identical to carbamoyl phosphate synthetase I deficiency. * However, increased ornithine with normal urea cycle enzymes suggests hereditary N-acetylglutamate deficiency.

Answer 6

* Definition * Most common urea cycle disorder. * X-linked recessive (vs. other urea cycle enzyme deficiencies, which are autosomal recessive). * Interferes with the body’s ability to eliminate ammonia. * Often evident in the first few days of life, but may present with late onset. * Excess carbamoyl phosphate is converted to orotic acid (part of the pyrimidine synthesis pathway). * Findings * Increased orotic acid in blood and urine, decreased BUN, symptoms of hyperammonemia. * No megaloblastic anemia (vs. orotic aciduria).

Answer 7

* Phenylalanine * --\> [BH4] --\> Tyrosine * --\> Thyroxine * --\> [BH4] --\> Dopa * --\> Melanin * --\> [B6] --\> Dopamine --\> [Vitamin C] --\> NE --\> [SAM] --\> Epi * Tryptophan * --\> [B6] --\> Niacin --\> NAD+ / NADP+ * --\> [BH4, B6] --\> Serotonin --\> Melatonin * Histidine * --\> [B6] --\> Histamine * Glycine * --\> [B6] --\> Porphyrin --\> Heme * Glutamate * --\> [B6] --\> GABA * --\> Glutathione * Arginine * --\> Creatine * --\> Urea * --\> [BH4] --\> Nitric oxide

Answer 8

* Definition * Due to decreased phenylalanine hydroxylase or decreased tetrahydrobiopterin cofactor (malignant PKU). * Tyrosine becomes essential. * Increased phenylalanine leads to excess phenylketones in urine. * Autosomal recessive. * Incidence ≈ 1:10,000. * Screened for 2–3 days after birth (normal at birth because of maternal enzyme during fetal life). * Findings * Intellectual disability, growth retardation, seizures, fair skin, eczema, musty body odor. * Disorder of **aromatic **amino acid metabolism --\> musty body **odor**. * Treatment * Decreased phenylalanine and increased tyrosine in diet. * PKU patients must avoid the artificial sweetener aspartame, which contains phenylalanine. * **Maternal PKU** * Lack of proper dietary therapy during pregnancy. * Findings in infant: microcephaly, intellectual disability, growth retardation, congenital heart defects. * Phenylketones * Phenylacetate, phenyllactate, and phenylpyruvate.

Answer 9

* Definition * Congenital deficiency of homogentisate oxidase in the degradative pathway of tyrosine to fumarate. * Autosomal recessive. * Benign disease. * Findings * Dark connective tissue, brown pigmented sclerae, urine turns black on prolonged exposure to air. * May have debilitating arthralgias (homogentisic acid toxic to cartilage).

Answer 10

* Types (all autosomal recessive): * Cystathionine synthase deficiency * Treatment: decrease methionine, increase cysteine, increase B12 and folate in diet * Decreased affinity of cystathionine synthase for pyridoxal phosphate * Treatment: really increased B6 and increased cysteine in diet * Homocysteine methyltransferase (methionine synthase) deficiency * Treatment: increased methionine in diet * All forms result in excess homocysteine. * Findings * Really increased homocysteine in urine, intellectual disability, osteoporosis, tall stature, kyphosis, lens subluxation (downward and inward), thrombosis, and atherosclerosis (stroke and MI).

Answer 11

* Definition * Hereditary defect of renal PCT and intestinal amino acid transporter for **_C_**ysteine, **_O_**rnithine, **_L_**ysine, and **_A_**rginine (**_COLA_**). * Cystine is made of 2 cysteines connected by a disulfide bond. * Excess cystine in the urine can lead to precipitation of hexagonal cystine stones. * Autosomal recessive. * Common (1:7000). * Diagnosis * Urinary cyanide-nitroprusside test is diagnostic. * Treatment * Urinary alkalinization (e.g., potassium citrate, acetazolamide) and chelating agents increase solubility of cystine stones * Good hydration.

Answer 12

* Definition * Blocked degradation of **_branched_** amino acids (**_I_**soleucine, **_L_**eucine, **_V_**aline) due to decreased α-ketoacid dehydrogenase (B1). * **_I_ **_L_**ove **_V_**ermont _maple syrup_ from maple trees (with _branches_).** * Autosomal recessive. * Findings * Causes increased α-ketoacids in the blood, especially those of leucine. * Causes severe CNS defects, intellectual disability, and death. * Urine smells like maple syrup/burnt sugar. * Treatment * Restriction of leucine, isoleucine, and valine in diet, and thiamine supplementation.

Answer 13

* Glycogen * Branches have α-(1,6) bonds * Linkages have α-(1,4) bonds. * A small amount of glycogen is degraded in lysosomes by α-1,4-glucosidase (acid maltase). * Skeletal muscle * Glycogen undergoes glycogenolysis --\> glucose-1-phosphate --\> glucose-6-P, which is rapidly metabolized during exercise. * Hepatocytes * Glycogen is stored and undergoes glycogenolysis to maintain blood sugar at appropriate levels. * Glycogen phosphorylase cleaves glucose-1-P residues off branched glycogen until four remain before a branch point. * Then 4-α-d-glucanotransferase (debranching enzyme [5]) moves three glucose-1-Ps from the branch to the linkage. * Then α-1,6-glucosidase (debranching enzyme[6]V) cleaves off the last glucose-1-P on the branch. * “Limit dextrin” refers to the one to four residues remaining on a branch after glycogen phosphorylase has already shortened it.

Answer 14

* Glycogen storage diseases * 12 types, all resulting in abnormal glycogen metabolism and an accumulation of glycogen within cells. * ****_V_**ery **_P_**oor **_C_**arbohydrate **_M_**etabolism.** * **_V_**on Gierke disease (type I) * **_P_**ompe disease (type II) * **_C_**ori disease (type III) * **_M_**cArdle disease (type V) * Lysosomal storage diseases * Each is caused by a deficiency in one of the many lysosomal enzymes. * Results in an accumulation of abnormal metabolic products. * Increased incidence of Tay-Sachs, Niemann-Pick, and some forms of Gaucher disease in Ashkenazi Jews.

Answer 15

* Type * Glycogen storage diseases (type I) * Autosomal recessive. * Findings * Severe fasting hypoglycemia, increased glycogen in liver, increased blood lactate, hepatomegaly * Deficient Enzyme * Glucose-6-phosphatase * Treatment * Frequent oral glucose/cornstarch; avoidance of fructose and galactose.

Answer 16

* Type * Glycogen storage disease (type II) * Autosomal recessive. * Findings * Cardiomyopathy and systemic findings leading to early death * Deficient Enzyme * Lysosomal α-1,4-glucosidase (acid maltase) * Comments * **_P_**ompe trashes the **_P_**ump (heart, liver, and muscle).

Answer 17

* Type * Glycogen storage disease (type III) * Autosomal recessive. * Findings * Milder form of type I with normal blood lactate levels * Deficient Enzyme * Debranching enzyme (α-1,6-glucosidase) * Comments * Gluconeogenesis is intact.

Answer 18

* Type * Glycogen storage disease (type V) * Autosomal recessive. * Findings * Increased glycogen in muscle, but cannot break it down, leading to painful muscle cramps, myoglobinuria (red urine) with strenuous exercise, and arrhythmia from electrolyte abnormalities. * Deficient Enzyme * Skeletal muscle glycogen phosphorylase (myophosphorylase) * Comments * **_M_**cArdle = **_M_**uscle.

Answer 19

* Type * Lysosomal storage disease: sphingolipidose * Findings * Peripheral neuropathy of hands/feet, angiokeratomas, cardiovascular/renal disease * Deficient Enzyme * α-galactosidase A * Accumulated Substrate * Ceramide trihexoside * Inheritance * XR

Answer 20

* Type * Lysosomal storage disease: sphingolipidose * Findings * Most common. * Hepatosplenomegaly, pancytopenia, aseptic necrosis of femur, bone crises, Gaucher cells [A] (lipid-laden macrophages resembling crumpled tissue paper) * Treatment * Recombinant glucocerebrosidase. * Deficient Enzyme * Glucocerebrosidase (β-glucosidase) * Accumulated Substrate * Glucocerebroside * Inheritance * AR

Answer 21

* Type * Lysosomal storage disease: sphingolipidose * **_No man picks_ (_Niemann-Pick_) his nose with his **_sphing_**er (**_sphing_**omyelinase).** * Findings * Progressive neurodegeneration, hepatosplenomegaly, “cherry-red” spot on macula, foam cells (lipidladen macrophages) [B] * Deficient Enzyme * Sphingomyelinase * Accumulated Substrate * Sphingomyelin * Inheritance * AR

Answer 22

* Type * Lysosomal storage disease: sphingolipidose * Findings * Progressive neurodegeneration, developmental delay, “cherry-red” spot on macula [C], lysosomes with onion skin, no hepatosplenomegaly (vs. Niemann-Pick) * Deficient Enzyme * Hexosaminidase A * **Tay-Sa**_X_** lacks he**_X_**osaminidase.** * Accumulated Substrate * GM2 ganglioside * Inheritance * AR

Answer 23

* Type * Lysosomal storage disease: sphingolipidose * Findings * Peripheral neuropathy, developmental delay, optic atrophy, globoid cells * Deficient Enzyme * Galactocerebrosidase * Accumulated Substrate * Galactocerebroside, psychosine * Inheritance * AR

Answer 24

* Type * Lysosomal storage disease: sphingolipidose * Findings * Central and peripheral demyelination with ataxia, dementia * Deficient Enzyme * Arylsulfatase A * Accumulated Substrate * Cerebroside sulfate * Inheritance * AR

Answer 25

* Type * Lysosomal storage disease: mucopolysaccharidose * Findings * Developmental delay, gargoylism, airway obstruction, corneal clouding, hepatosplenomegaly * Deficient Enzyme * α-L-iduronidase * Accumulated Substrate * Heparan sulfate, dermatan sulfate * Inheritance * AR

Answer 26

* Type * Lysosomal storage disease: mucopolysaccharidose * Findings * Mild Hurler + aggressive behavior, no corneal clouding * Deficient Enzyme * Iduronate sulfatase * Accumulated Substrate * Heparan sulfate, dermatan sulfate * Inheritance * XR * **_Hunters_ see _clearly_ (_no corneal clouding_) and aggressively aim for the _X_ (_X_-linked recessive).**

Answer 27

* Long-chain fatty acid degradation requires... * Carnitine-dependent transport into the mitochondrial matrix. * ****_CAR_**nitine = **_CAR_**nage of fatty acids.** * **Carnitine deficiency** * Inability to transport LCFAs into the mitochondria, resulting in toxic accumulation. * Causes weakness, hypotonia, and hypoketotic hypoglycemia. * **Acyl-CoA dehydrogenase deficiency** * Increased dicarboxylic acids, decreased glucose and ketones. * Acetyl-CoA is a (+) allosteric regulator of pyruvate carboxylase in gluconeogenesis. * Decreased acetyl-CoA --\> decreased fasting glucose. * **“**_SY_**trate” = **_SY_**nthesis.**

Answer 28

* In the liver... * Fatty acids and amino acids are metabolized to acetoacetate and β-hydroxybutyrate (to be used in muscle and brain). * Other situations * In prolonged starvation and diabetic ketoacidosis... * Oxaloacetate is depleted for gluconeogenesis. * In alcoholism... * Excess NADH shunts oxaloacetate to malate. * Both processes cause... * A buildup of acetyl-CoA, which shunts glucose and FFA toward the production of ketone bodies. * Breath * Smells like acetone (fruity odor). * Urine test for ketones * Does not detect β-hydroxybutyrate.

Answer 29

* 1 g protein or carbohydrate = 4 kcal. * 1 g fat = 9 kcal. * 1 g alcohol = 7 kcal.

Answer 30

* Priorities * Supply sufficient glucose to the brain and RBCs * Preserve protein. * Fed state (after a meal) * Glycolysis and aerobic respiration. * Insulin stimulates storage of lipids, proteins, glycogen. * Fasting (between meals) * Hepatic glycogenolysis (major) * Hepatic gluconeogenesis, adipose release of FFA (minor). * Glucagon, adrenaline stimulate use of fuel reserves. * Starvation days 1–3 * Blood glucose levels maintained by: * Hepatic glycogenolysis * Adipose release of FFA * Muscle and liver, which shift fuel use from glucose to FFA * Hepatic gluconeogenesis from peripheral tissue lactate and alanine, and from adipose tissue glycerol and propionyl- CoA (from odd-chain FFA—the only triacylglycerol components that contribute to gluconeogenesis) * Glycogen reserves depleted after day 1. * RBCs lack mitochondria and so cannot use ketones. * Starvation after day 3 * Adipose stores (ketone bodies become the main source of energy for the brain). * After these are depleted, vital protein degradation accelerates, leading to organ failure and death. * Amount of excess stores determines survival time.

Answer 31

* Rate-limiting step is catalyzed by HMG-CoA reductase (induced by insulin), which converts HMG-CoA to mevalonate. * 2⁄3 of plasma cholesterol is esterified by lecithin-cholesterol acyltransferase (LCAT). * Statins (e.g., lovastatin) competitively and reversibly inhibit HMG-CoA reductase.

Answer 32

* Pancreatic lipase * Degradation of dietary triglycerides (TG) in small intestine. * Lipoprotein lipase (LPL) * Degradation of TG circulating in chylomicrons and VLDLs. * Found on vascular endothelial surface. * Hepatic TG lipase (HL) * Degradation of TG remaining in IDL. * Hormone-sensitive lipase * Degradation of TG stored in adipocytes. * LCAT * Catalyzes esterification of cholesterol. * Cholesterol ester transfer protein (CETP) * Mediates transfer of cholesterol esters to other lipoprotein particles.

Answer 33

* E * _Function_: Mediates remnant uptake * Chylomicron & Chylomicron remnant * VLDL, IDL, & HDL * A-I * _Function_: Activates LCAT * Chylomicron * HDL * C-II * _Function_: Lipoprotein lipase cofactor * Chylomicron * VLDL & HDL * B-48 * _Function_: Mediates chylomicron secretion * Chylomicron & Chylomicron remnant * B-100 * _Function_: Binds LDL receptor * VLDL, IDL, & LDL

Answer 34

* Lipoproteins are composed of... * Varying proportions of cholesterol, TGs, and phospholipids. * What carry most cholesterol * LDL and HDL carry most cholesterol. * Chylomicron * Delivers dietary TGs to peripheral tissue. * Delivers cholesterol to liver in the form of chylomicron remnants, which are mostly depleted of their triacylglycerols. * Secreted by intestinal epithelial cells. * VLDL * Delivers hepatic TGs to peripheral tissue. * Secreted by liver. * IDL * Formed in the degradation of VLDL. * Delivers TGs and cholesterol to liver. * LDL * Delivers hepatic cholesterol from liver to peripheral tissues. * Formed by hepatic lipase modification of IDL in the peripheral tissue. * Taken up by target cells via receptor-mediated endocytosis. * ****_L_**DL is **_L_**ousy.** * 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. * Alcohol increases synthesis. * ****_H_**DL is **_H_**ealthy.**

Answer 35

* Hyper-chylomicronemia * Type I * Increased blood level * Chylomicrons, TG, cholesterol * Pathophysiology * Autosomal recessive. * Lipoprotein lipase deficiency or altered apolipoprotein C-II. * Causes pancreatitis, hepatosplenomegaly, and eruptive/pruritic xanthomas (no risk for atherosclerosis). * Familial hyper-cholesterolemia * Type IIa * Increased blood level * LDL, cholesterol * Pathophysiology * Autosomal dominant. * Absent or defective LDL receptors. * Heterozygotes (1:500) have cholesterol ≈ 300 mg/dL * Homozygotes (very rare) have cholesterol ≈ 700+ mg/dL. * Causes accelerated atherosclerosis (may have MI before age 20), tendon (Achilles) xanthomas, and corneal arcus. * Hyper-triglyceridemia * Type IV * Increased blood level * VLDL, TG * Pathophysiology * Autosomal dominant. * Hepatic overproduction of VLDL. * Causes pancreatitis.

Biochemistry - Metabolism Flashcards

(62 cards)