Chapter 17

Question 1

Where is body protein catabolized?

Answer 1

muscle and liver

Question 2

What happens to breakdown products of protein?

Answer 2

amino acids released from proteins lose their amino group through transamination or deamination

carbon skeletons converted in liver to glucose (glucogenic amino acids), acetyl CoA, and ketone bodies (ketogenic)

some cases–glucogenic and ketogenic amino acids can be produced

Question 3

How is nitrogen excreted?

Answer 3

eliminated from body in urine

kidney adds somes ammonium ion to urine to regulate acid base balance and eliminate nitrogen

excess nitrogen converted to urea in liver and goes through blood to kidney

amino groups released by deamination reactions form ammonium ion (NH4+)

–if escape in peripheral blood cause hyperammonemia: toxic effects on brain (cerebral edema, convulsions, coma, and death)

most tissues: add excess nitrogen to blood as glutamine by attaching ammonia to gamma carboxyl group of glutamate

muscle sends nitrogen to liver as alanine and some glutamate

Question 4

What is the scematic of nitrogen being excreted?

Answer 4

as urea and ammonia

Question 5

What is gluatmine synthase?

Answer 5

in most tissues, including muscle

captures excess nitrogen by aminating glutamate to form glutamine

irreversible

glutamine=nontoxic; major carrier of excess nitrogen from tissues

Question 6

What is glutaminase?

Answer 6

in kidney

deaminates glutamine arriving in blood and eliminate amino group as ammonium ion in urine

irreversible

indcued by chronic acidosis–excretion of ammonium major defense mechanism

small amounts in liver

high in intestine

ammonium ion from deamination (intestinal bacterial and glutamine from dietary protein) is sent to liver via portal blood and use for urea synthesis

Question 7

What is aminotransferase (transaminase)?

Answer 7

in liver and muscle

transfers amino group form one carbon skeleton (amino acid) to another (alpha ketoglutarate, citric acid cycle intermediate)

Pyridoxal phosphate (PLP) from vitamin B6 is required to mediate transfer

alanine aminotransferase (ALT, GPT) and aspartate aminotransferase (AST, GOT)

pathology conditions: enzymes leak into blood; clinical sign of damage to muscle or liver

Question 8

What is the role of aminotransferase in metabolism?

Answer 8

reversible reaction

protein catabolism in muscle: move amino groups from amino acids onto glutamate–pooling it for transport

glutamate can be aminated by glutamine synthase or transfer amino group to pyruvate forming alanine using aminotransferase ALT

liver: aminotransferases ALT and AST an move amino group from alanine arriving from muscle into aspartate–direct donor of nitrogen into urea cycle

Question 9

What is glutamate dehydrogenase?

Answer 9

enzyme in many tissues

catalyzes the reversible oxidative deamination of the amino acid glutamate

produces alpha ketoglutarate

Question 10

What is the urea cycle?

Answer 10

urea: has two nitrogens

synthesized in liver from aspartate and carbamoyl phosphate

–produced from ammonium ion and CO2 by mitochondrial carbamoyl phosphate synthetase

–enzymes requires N-acetylglutamate as activator

N-acetylglutamate only produced when free amino acids present

Question 11

Where does the urea cycle occur?

Answer 11

occurs in mitochondria and cytoplasm

citrulline enters cytoplasm and ornithine returns to mitochondria

carbamoyl phosphate synthetase and ornithine transcarbamoylase: mitochondrial enzymes

aspartate enters cycle in cytoplasm and leaves cycle (minus amino group) as fumarate–if gluconeogenesis active, fumarate can be converted to glucose

produce urea is formed in cytoplasm and enters blood for delivery to kidney

Question 12

What are signs of a defect in the ure cycle?

Answer 12

hyperammoniemia, elevated blood glutamine, decreased blood urea nitrogen (BUN)

Question 13

What occurs in neonatal onset of urea cycle deficiency?

Answer 13

appear normal for 24 hours

24-72 postnatal period: lethargy, vomiting, hyperventilation; progress to coma, respiratory failure and death

Question 14

What is the difference between ornithine transcarbamoylase deficiency and carbamoyl phosphate synthase?

Answer 14

ornithine transcarbamoylase deficiency: increase in orotic acid and uracil

–intermediates in pyrimidine synthesis

–stimulated by accumultion of cabamoyl phosphate (substrate for ornithine transcarbamoylase in urea cycle and aspartate transcarbamoylase in pyrimidine synthesis)

Question 15

How do you treat genetic deficiencies in the urea cycle?

Answer 15

low protein diet

administration of sodium benzoate and phenylpyruvate to provide altenrative route for capturing and excreting excess nitrogen

Question 16

What is the difference between genetic deficiencies iin carbamoyl phosphate synthetase and ornithine transcarbamoylase?

Answer 16

Question 17

What is the urea cycle schematic?

Answer 17

Question 18

What is the schematic of amino acid metabolism?

What are the asosciated deficiencies?

Answer 18

Question 19

What is phenylalanine hydroxylase deficiency?

Answer 19

phenylketonuria (PKU)

–normal at birth

–untreated and show slow development, severe mental retardation, autistic symptoms, and loss of motor control

–pale skine, white-blone hair

–neurotoxic effects becuase high levels of phenylalanine

treatment: life long semisynthetic diet restricted in phenylalanine (small quantities necessary because essential amino acid)

aspartame (N-aspartyl-phenylalanine methyl ester): artificial sweetener must be avoided

Question 20

What occurs with pregnant women with PKU and their babies?

Answer 20

must be careful about phenylalanine levels in blood so don’t adversely affect neurologic development in fetus

infants have high risk for mental retardation (less profound than child with untreated PKU), microcephaly, and low birth weight

Question 21

What is homogentisate oxidase deficiency?

Answer 21

accumulation of homogentisic acid in blood causes excretion in urine

alcaptonuria–urine gradually darkens upon exposure to air

dark pigment also accumulates over years in cartilage; may be seen in sclera of eye, in ear cartilage

patients develop arthritis in adulthood

treamtent: managing symptoms

Question 22

What is brancehd chain ketoacid dehydrogenase deficiency?

Answer 22

maple syrup urine disease

branched chain ketoacid dehydrogenase: metabolizes branched chain ketoacids produced from their cognate amino acids (valine lecuine and isoleucine)

requires thiamine, lipoic acid, CoA, FAD, NAD+

infants normal for a few days; progressively lethartgic, lose weight, alternating episodes of hypertonia, hypotonia

urine has characteristic odor of maple syrup

ketosis coma and death if not treated

tratment: restricting dietary valine, leucine and isoleucine

Question 23

What is propionyl CoA carboxylase and methylmalonyl CoA mutase deficiences?

Answer 23

valine, methionine, isoleucine and threonin e=metabolized thorugh propionic acid pathwya

–causes neonatal ketoacidosis from failure to metabolize ketoacids produced from four amino acids

treatment: diet low in protein, semisynthetic diet wiht low amounts of valine, methionine, isoleucine and threonine

Question 24

What is the difference between propionyl CoA carboxylase deficiency and methylmalonyl CoA mutase deficiency?

Answer 24

propionyl CoA carboxylase: accumulation of propionic acid, methyl citrate, hydroxylpropionic acid

methylmalonyl CoA mutase: accumulase of methylmalonic acid

Question 26

What is homocystinemia/homocystinuria?

Answer 26

accumulation of homocystine and methionine in the blood and urine associated with cardiovascular disease, deep vein thrombosis, thromboembolism, and stroke, dislocation of lens (ectopic lens), and mental retardation, long spidery fingers atherosclerosis in children myocardial infarction by 20 years of age excrete high levels of homocystine in urine treatment: diet low in methionine enzyme deficiency: cystathionine synthase die from myocardial infarction, stroke, pulmonary embolism

Question 27

What is the clinical difference between Marfan syndrome and homocystinemia?

Answer 27

Marfan: defect in fibrillin gene tall stature, long fingers and toes, lens dislocation, tendency toward aortic wall ruptures subluxation of lens is upward and outward homocystinemia: subluxation of lens is downward and inward

Question 28

What vitamin deficiencies cause homocystinemia?

Answer 28

more mild form increased risk for atherosclerosis, deep vein thrombosis, stroke folate deficiency, vitamin B12, vitamin B6

Question 29

What is S-adenosylmethionine (SAM)?

Answer 29

methyl donor required in synthesis of epinephrine and 7-methylguanine cap on eukaryotic mRNA --after donating methyl group, SAM is converted to homocysteine and remethylated by N-methyl THF homocysteine methyltransferase --requires B12 and N-methyl THF

Question 30

What is tetrahydrofolate (THF)?

Answer 30

methylene, methenyl, formyl donor formed from vitamin folate catalyzed by hydrofolate reductase purine and thymidine synthesis requires THF --DNA and RNA synthesis during cell growht and division

Question 31

What causes megoblastic anemia?

Answer 31

insufficient active THF to support cell division in bone marrow

Question 32

What is methotrexate?

Answer 32

inhibits DHF reductase antineoplastic drug

Question 33

Where is folate stored?

Answer 33

folate deficiencies in pregnancy and alcoholics stores as highly reduced N5-methyl-THF converted into THF by N-methyl THF homocysteine methyltransferase --requires B12

Question 34

What is cobalamin?

Answer 34

vitamin B12 reduced and activated in body to adenosylcobalamine (used by methylmalonyl CoA mutagse) and methylcobalamin (formed from N5-methyl THF in N-methyl THF homocysteine methyl transferase reaction

Question 35

What is result of B12 deficiency?

Answer 35

can cause secondary deficit of active THF by preventing released from storage pool through N-methyl THF homocysteine methyltransferase reaction --can result in megaloblastic enamia --progressive peripheral neurophathy also caused by cobalamin deficiency treating deficiency with folate correct megaloblastic anemia but not neuropathy

Question 36

What is reason of cobalamin deficiency?

Answer 36

pernicious anemia: failure to absorb vitamin B12 in absence of intrinsic factor from parietal cells vitamin B12 abosrption also decreases with agin and in individuals with chronic pancreatitis less common: long term vegetarian diets, infection with Diphyllobothrium latum (parasite in raw fish) excess B12 is stored in body so deficiencies develop slowly

Question 37

What is the difference between a folate and vitamin B12 deficiency?

Answer 37

Question 38

Whta are the products of amino acids tyrosine, tryptophan, arginine, glutamate, histidine?

Answer 38

Question 39

What is heme synthesis?

Answer 39

occurs in most tissues heme proteins include hemoglobin, myoblobin, cytochromes (ETC, cytochrome P450, cytochrome b5), enzymes catalase, peroxidase, guanylate cycase stimulated by NO in liver: rate lmiting enzyme delta-aminoevulinate synthase (ALA) is repressed by heme

Question 40

What are the steps of heme synthesis?

Answer 40

Question 41

What do the -ogen and -in suffixes mean?

Answer 41

ogen: colorless in presence of oxygen, they oxidize and form conjugated double bond network in compound, which are highly colored substances in: highly colored

Question 42

What is acute intermittent porphyria?

Answer 42

porphobilinogen deminase (hydroxymethylbilane synthase) deficiency late onset autosomal dominant disease heterozygotes: symptom free throughout live symptoms: abdominal pain (multiple laproscpies; scars on abdomen), anxiety, paranoia, depression, paralysis, motor, sensory or autonomic neuropathy, weakness, excretion of ALA (delta-aminolevulinic) and PBG (porphobilinogen) during episodes severe: port wine color urine on standing

Question 43

What are porphyrias?

Answer 43

photosensitivity, chronic inflammation to overt blistering and shearing in exposed areas of skin common: porphyria cutanea tarda beta carotene often give to porphryia pateints with photosensitivity to reduce prodcution of reactive oxygen species

Question 44

What is porphyria cutanea tarda?

Answer 44

deficiency of uroporphyrinogen decarboxylase autosomal dominant disease with late onset adult onset hepatic porphyria hepatocytes unable to decarboxylate uroporphyrinogen in heme synthesis uroporphyrin spills out of liver and into urine red wine urine hepatotoxic substances (excessive alcohol and iron deposites) can make disease worse skin lesions becuase high circulating porphyrins

Question 45

What is result of B6 deficiency?

Answer 45

ALA synthase: rate limiting enzye, requires pyridoxine (vitamin B6) deficiency of pyridoxine associated with isoniazid therapy for TB and may cause sideroblastic anemia with ringed sideroblasts

Question 46

What is result of iron deficiency?

Answer 46

heme synthase (ferrochelatase) introduces Fe2+ into heme ring deficiency of iron produces microcytic hypochromic anemia

Question 47

What is effect of barbituates on porphyrins?

Answer 47

barbiturates are hydroxylated by microsomal cytochrome P450 system inliver to facilitate their efficient elmination from body administration of barbiturates results in stimulation of cytochrome P450 synthesis, which in turn reduces heme levels reduction in heme lessens repression of ALA synthase causing more porphyrin recursor syntehsis in porphyrias, indirect production of more precursosrs by barbiturates exacerbates the disease

Question 48

What is result of lead poisoning?

Answer 48

lead inactivates many enzymes including ALA dehydrase and ferrochelatase (heme synthase) produce microcytic sideroblastic anemia with ringed sideroblasts in bone marrow symptoms: coarse basophilic stippling of erythrocytes; headache, nausea, memory loss, abdominal pain, diarrhea (lead colic), lead lines in gums, lead deposits in abdomen and epiphyses of bone seen on radiograph, neuropathy (claw hand, wrist drop), increased urinary ALA, increased free erythrocyte protoporphyrin

Question 49

What is difference between vitamin B6 deficiency, iron deficiency, and lead poisoning?

Answer 49

all can cause anemia

Question 50

What happens when ferrochelatase doesn't function

Answer 50

if ferrochelatase doesn't insert Fe2+ into protoporhyrin IX to form heme (in lead poisoning, iron deficiency anemia) it results in nonenzymatic insertion of Zn2+ to form zinc protoporphyrin --complex is extremely fluorescent and is easily detected

Question 51

What is hemochromatosis?

Answer 51

inherited autosomal recessive disease men \> 40 yo and older women dialy intestinal absorption of 2-3 mg of iron compared with normal 1 mg over 20-30 years, disease results in levels of 20-30 grams of iron in boyd compared with normal 4 hemosiderin deposits are found in liver, pancreas, skin and joints

Question 52

How is iron transported and stored?

Answer 52

iron (Fe3+) released from hemoglobin in histiocytes is bound to ferrritin and then transported in blood by transferrin, which can deliver it to tissues for synthesis of heme --ferroxidase: ceruloplasmin (Cu2+ protein) oxidizes Fe2+ to Fe3+ for transport and storage --transferrin carries Fe3+ in blood --ferritin oxidizes Fe2+ to Fe3+ for storage of normal amounts of Fe3+ in tissues; loss of iron ffrom body is accomplished by sleeding and shedding epithelial cells of mucosa and skin; body has no mechanism for excreting iron so controlling absorption into mucosal cells is crucial --hemosiderin binds excess Fe3+ to prevent escape of free Fe3+ into blood, where its toxic

Question 53

What is bilirubin metabolism?

Answer 53

subsequent to lysis of older erythrocytes in spleen, heme released from hemoglobin is converted to bilirubin in histiocytes --bilirubin not water soluble and thus is transported in blood attached to serum albumin --hepatocytes conjugate bilirubin with glucuronic acids, increasing its water solubility --conjugated bilirubin is secreted into bile --intesitnal bacteria convert conjugated bilirubin into urobilinogen --portion of urobilinogen is further converted to bile pigments (stercobilin) and excreted in feces, producing characteristic red-brown color; bile duct obstruction results in clay colored stools --some of urobilinogen is converted to urobilin (yellow) and excreted in urine

Question 54

What occurs in hemolytic anemia and bilirubin?

Answer 54

excessive RBC destruction in hemolytic anemia results in excessive conersion of bilirubin to urobilinogen in intestine higher than normal absorption of urobilinogen and its subsequent excretion in urine results in deeper color urine

Question 55

What is jaundice?

Answer 55

yellow color of skin and whites of eyes occurs when blood levels of bilirubin exceed normal (icterus) characterized by increased in unconjugated (indirect) bilirubin, conjugated (direct) bilirubin, or both accumulation of bilirubin (usually unconjugated) in brain (kernicterus) may result in death wehn conjugated bilirubin increased, it may be excreted giving deep yellow red color to urine

Question 56

What is hemolytic crisis?

Answer 56

associated with increased bilirubin and jaundice with severe hemolysis, more bilirubin is released into blood than can be transported on albumin and conjugated in liver unconjugated and total bilirubin increase and may porduce jaundice and kernicterus examples: episode of hemolysis in G6PDH deficiency, sickle cell criss, Rh disease of newborn crisis confirmed by low hemoglobin and elevated reticulocyte counts

Question 57

What is UDP glucuronyl transferase deficiency?

Answer 57

bilirubin conjugation is low becuase of genetic or fucntional deficiency of the glucuronyl transferase system, unconjugated and total bilirubin increase examples: Crigler-Nijjar syndrome, Gilbert syndrome, physiologic jaundice in newobrn, especially premature infants (enzyems not fully induced)

Question 58

What is hepatic damage and bilirubin associated?

Answer 58

viral hepatitis or cirrhosis prodcues increase in both direct and indirect bilirubin aminotransferase levels elevated alchoolic liver disease: AST increased more than ALT viral hepatitis: ALT increased more than AST

Question 59

What occurs with bile duct occlusion?

Answer 59

by gallstone, primary biliary cirrhosis, pancreatic cancer prevents conjugated bilirubin from leaving liver conjugated bilirubin increases in blood and may appear in urine feces are light colored