17 Aminoacid Metabolism Flashcards
Hartnup Disease mechanism and symptoms
Defective transport in intestine and kidney of large neutral aminoacids
including Trp
Pellagra like symptoms: Dermatitis, Dementia, Diarrhea
mechanism and symptoms Cystinuria
Treatment
Defect transport in intestine and Kidney of Basic aminoacids: Lysine and arginine
Cystine: Disulfide dimer of cystein > insoluble in water cause Stone & Infecton
Treatment with Acetazolamide ↑urinary pH become more soluble or penicillamine to combine it
hyperammonemia results
Toxic effects onthe brain (cerebral edema, convulsions, coma, and death)
Alkalinize the blood
Liver ammonia income
Ammonia form from portal blood
Alanine form from Muscles (mostly) and other tissues
Smaller quantities of other amino acids, in addition to glutamine
Kidney ammonia income
what happen in kidney
Mostly in form of glutamine from other tissues
Glutaminase release NH3 from glutamine
Intestine ammonia income
Intestinal bacteria
Glutamine from dietary protein
Tissue Glutamines
Where does Glutaminase work
kidney : irreversible
Kidney glutaminase is induced by chronic acidosis
The liver has only small quantities of glutaminase
Intestine: ammonium ion from deamination can be sent directly to the liver via the portal blood
where does glutamate dehydrogenase work
what is the product
Catalyzes the oxidative deamination of glutamate
reversible : make NADH
Produces a-ketoglutarate
where does aminotransferases work
what is the co enzyme
Both muscles and liver: AST just in liver Pyridoxal phosphate (PLP) derived from vitamin B6 is Coenzyme
Urea in liver produced from which nitrogens
Ammonia directly taken from portal blood
Ammonia produced from Glutamate by glutamate dehydrogenase
Aspartate produced from adding an amino group to oxaloacetate (AST)
Most tissues nitrogen destiny
Glutamine synthetase
Captures excess nitrogen by aminating glutamate to form glutamine
irreversible
Ammonia become available through deaminations
How does alanine produced in muscles
which enzyme and substrate and coenzyme are involved
aminogroup transfer to a ketoglutarate to form glutamate
aminogroup transfer from glutamate to pyruvate to form alanine (ALT)
B6 is co enzyme
what does Urea produced from in mitochondria
Carbamoyl phosphate: Produced from ammonium ion and Carbon dioxide: by Mitochondrial carbamoyl phosphate synthetase I
Aspartate added outside mitochondria
what is the coenzyme of carbamoyl phosphate synthetase I
N-Acetylglutamate
Obligate activator
Produced only when free amino acids are present
name two Obligate activators of enzymes
N-acetylglutamate in carbamoyl phosphate synthetase I
Acetyl coA in pyruvate carboxylase
name the enzymes of intramitochondrial urea cycle and their products
Carbamoyl Phosphate Synthetase : carbamoyl phosphate
Ornithine Transcarbamoylase : Citrulline
primary substrate of urea cycle
NH4 HCO3 2ATP : carbamoyl phosphate
cytoplasmic steps of urea cycle
Citrulline with aspartate and ATP by Argininosuccinate Synthetase to Argininosuccinate
then by Argininosuccinate Lyase to arginine and release fumarate
then by arginase to ornithine and releas urea
what kind of aminoacid is Arginine
Essential only in positive nitrogen balance situation like children
it should help in making new histones
Symptoms of defect in the urea cycle
combination of hyperammonemia, elevated blood glutamine, and decreased BUN
Symptoms of neonatal onset urea cycle defects
Infants typically appear normal for the first 24 hours
During the 24- to 72-hour postnatal period, symptoms of lethargy, vomiting, and hyperventilation begin
if not treated, progress to coma, respiratory failure, and death
Carbamoyl Phosphate Synthetase deficiency symptoms and features
↑[NH4+], hyperammonemia
Blood glutamine is increased
BUN is decreased
No orotic aciduria
Autosomal Recessive
Cerebral edema
Lethargy, convulsions, coma, death
Ornithine Transcarbamoylase deficiency symptoms and features
↑[NH4+], hyperammonemia
Blood glutamine is increased
BUN is decreased
Orotic aciduria
X-linked recessive
Cerebral edema
Lethargy, convulsions, coma, death
what is the mechanism of orotic aciduria
↑carbamoyl phosphate in cytoplasm
Substrate for aspartate transcarbamoylase in pyrimidine Synthesis
↑orotic acids
Treatment of defects in urea cycle
Low protein diet
administration of sodium benzoate or phenylpyruvate
provide an alternative route for capturing and excreting excess nitrogen
Phenylketonuria etiology
Phenylalanine Hydroxylase Deficiency
Tetrahydrobiopterin ( a coenzyme) Deficiency
PKU symptoms and prevention
Infants normal at birth
If untreated show slow development, severe mental retardation, Musty odor in diaper ,autistic symptoms, and loss of motor control
Children may have pale skin and white-blonde hair > Lack of tyrosine > no melanin
routinely screened a few days after birth for blood phenylalanine level
what is the etiology of neurotoxic effects in PKU
High levels of phenylalanine
not phenylketones
PKU treatment
Life-long semisynthetic diet Low in phenylalanine (small quantities are necessary : essential amino acid) and tyrosine supplements
Aspartame (N-aspartyl-phenylalanine methyl ester), an artificial sweetener, must be avoided
complications in pregnant PKU if not maintain metabolic control
mental retardation (less profound than a child with untreated PKU), microcephaly, and low birth weight
Alcaptonuria etiology
Homogentisate Oxidase Deficiency
Alcaptonuria symptoms
Dark urine
Ochronosis
Arthritis
Albinism etiology
Tyrosinase deficiency
no production of melanin
Maple Syrup Urine Disease etiology
Branched-Chain Ketoacid Dehydrogenase Deficiency
defect in CoA production
what are coenzymes for Branched-Chain Ketoacid Dehydrogenase and what other enzymes share them
thiamine, lipoic acid, CoA, FAD, NAD+
Pyruvate dehydrogenase, a-ketoglutarate dehydrogenase
What are Branched-Chain Ketoacid
produced from their cognate amino acids, valine, leucine, and isoleucine through deamination
Maple Syrup Urine Disease symptoms
normal for the first few days of life
become progressively lethargic, lose weight, and have alternating episodes of hypertonia and hypotonia, and the urine develops a characteristic odor of maple syrup
Ketosis, coma, and death ensue if not treated
what are propionic acid pathway enzymes deficiency
what substances accumulate in each
what aminoacids are involved
Propionyl-CoA Carboxylase Deficiency: Propionic acid, methyl citrate, hydroxypropionic acid
Methylmalonyl-CoA Mutase Deficiency: methylmalonic aciduria
Valine, methionine, isoleucine, and threonine
propionic acid pathway enzymes deficiency symptoms
neonatal ketoacidosis
methylmalonic aciduria can be present depending on the enzyme involved
what is co factor of Methylmalonyl-CoA Mutase
B12
what is co factor of Propionyl-CoA Carboxylase
Biotin
Homocystinemia/Homocystinuria etiology
Cystathionine synthase deficiency
Homocysteine methyltransferase deficiency
Methyltetrahydrofolate deficiency
what is co factor of Cystathionine synthase
B6
what is co factor of Homocysteine methyltransferase
Methyl THF
B12
How does homocystein produced
Methionine with adenosine produce S-adenosylmethionine(methyl donor)
then become S-adenosylhomocysteine
release adenosine and become homocystein
what will happen for homocystein
by cystathione synthase and B6 become cystathione
by homocysteine methyl transferase and B12 and methyl THF become methionine
where would the methyl group from S-adenosylmethionine be used
Epinephrine
N-methylguanine cap on mRNA
Homocystinemia/Homocystinuria Symptoms & treatment
cardiovascular disease, deep vein thrombosis, thromboembolism, and stroke, dislocation of the lens (downward and inward in contrast to marfan) and mental retardation
low in methionine
partial activity of cystathionine synthase respond well to pyridoxine administration
which Vitamin deficiencies would produce homocystinemia
Folate deficiency
Vitamin B12
Vitamin B6
produce a mild form of homocysteinemia
name a single carbon donor
tetrahydrofolate (THF)
how is THF produced
two reductions catalyzed by dihydrofolate reductase
where does Methotrexate affect
Methotrexate inhibits DHF reductase
what is the folate cycle
THF take one carbon unit, then gives it to purines and thymidine and become methyl THF
in the presence of B12 and homocysteine methyl transferase it will donate its methyl group and become THF
what is the mechanism of B12 deficiency in producing megaloblastic anemia
halting the folate cycle in methyl THF will result in loss of active folate
causes of folate deficiency
Pregnancy (neural tube defects in fetus may result)
Alcoholism
Severe malnutrition
causes of B12 deficiency
Pernicious anemia Gastric resection Chronic pancreatitis Severe malnutrition Vegan Infection with D. latum
features of folate deficiency
↑ homocysteine
↓ Methionine
features of B12 deficiency
↑ homocysteine
↓ Methionine
↑ methylmalonyl aciduria
features of B6 deficiency
↑ homocysteine
↑ Methionine
symptoms of Folate and B12 Deficiency
Macrocytic anemia
MCV>100
PMN nucleus more than 5 lobes
Homocystinemia with risk for cardiovascular disease
B12 deficiency specific symptoms
Methylmalonic aciduria
Progressive peripheral neuropathy
Deficiency develops in years
Folate deficiency specific symptoms
Deficiency develops in 3-4 months
cathecholamine synthesis pathway
Tyrosine by tyrosine hydroxylase and tetrahydrobiopterin to 3,4 dihydrophenylalanine (DOPA)
by DOPA decarboxylase and B6 to Dopamine
by Dopamine b-hydroxylase and VitC/Cu2+ to norepinephrine
by phenylethanolamine methyltransferase and s-adenosylmethionine to epinephrine
co enzyme for tyrosine hydroxylase
tetrahydrobiopterin THB
co enzyme for DOPA decarboxylase
B6
co enzyme for Dopamine b-hydroxylase
VitC/Cu2+
what is the dopaminergic drug used in parkinson
and why
L-dopa can cross BBB
catecholamines cannot enter the brain so brain synthetize them locally
where is heme needed
hemoglobin myoglobin
cytochromes (electron transport chain, cytochrome P-450, cytochrome b5)
enzymes catalase, peroxidase
soluble guanylate cyclase stimulated by nitric oxide
Rate limiting enzyme in heme synthesis in liver
what is its regulator
δ-aminolevulinate synthase (ALA)
repressed by heme
what is the first step of heme synthesis
what is co factor
what is its regulator
Glycine with succinyl coA by ALA synthase and B6 in mitochondria produce δ-aminolevulinic acid
repressed by heme
what are the steps in 1st part of heme synthesis
and what disease will happen if it goes wrong
ALA by ala dehdratase to prophobilinogen
by porphobilinogen deaminase to hydroxymethylbilane
this step can produce acute intermittent porphyria
by Uroporphyrinogen synthase to uroporphyrinogen
what are the steps in 2nd part of heme synthesis
and what disease will happen if it goes wrong
Uroporphyrinogen to coproporphyrinogen by Uroporphyrinogen decarboxylase
this step can produce porphyria cutanea tarda
then to protoporphyrin
protoporphyrin by Ferrochelatase to heme with Fe2+
which enzyme in heme synthesis can be inhibited by lead
ferrochelatase
ALA dehdratase
what is uroporphyrinogen significance
first porphyrin in heme synthesis
before this substance, enzyme disorder will not result in photosensitivity and cutaneous lesions
what are the symptoms of Acute intermittent porphyria
late-onset
autosomal dominant, variable expression
Abdominal pain, often resulting in multiple laparoscopies (scars on abdomen)
Anxiety, paranoia, and depression
Paralysis
Motor, Sensory or autonomic neuropathy
Weakness
Excretion of ALA (δ-aminolevulinic) and PBG (porphobilinogen) during episodes
In severe cases, dark port-wine color to urine on standing
which enzyme is problematic in Acute intermittent porphyria
what shouldnt be done in these patients
porphobilinogen deaminase
never give barbiturates
what’s the relationship between barbiturates and porphyria
Hydroxylated by the microsomal cytochrome P-4S0 system in the liver
Results in stimulation of cytochrome P-4S0 synthesis
reduces heme levels
lessens the repression of ALA synthase
more porphyrin precursor synthesis
Indirect production of more precursors by the barbiturates exacerbates the disease
what to administer in porphyria patients
β-Carotene is often administered to porphryia patients with photosensitivity to reduce the production of reactive oxygen species
what are the symptoms of Porphyria Cutanea Tarda
Most common porphyria
Autosomal dominant, late-onset hepatic porphyria
Photosensitivity
Inflammation, blistering, shearing of skin in areas exposed to light
Hyperpigmentation
Hepatotoxic substances, such as excessive alcohol or iron deposits, can exacerbate it
red-wine urine if it is allowed to stand
which enzyme is problematic in Porphyria Cutanea Tarda
what shouldnt be done in these patients
Uroporphyrinogen decarboxylase
avoiding alcohol
what is the result of Vitamin B6 deficiency in heme pathway
what will cause in its deficiency
ALA synthase, the rate-limiting enzyme, requires pyridoxine (vitamin B6)
Associated with isoniazid therapy for tuberculosis
may cause sideroblastic anemia with ringed sideroblasts
Ring sideroblasts is accumulation of Iron in the mitochondria of cell
what is the mechanism of Iron deficiency
The last enzyme in the pathway, heme synthase (ferrochelatase), introduces the Fe2+ into the heme ring
Deficiency of iron produces a microcytic hypochromic anemia
which enzymes are involved in lead Poisoning
what is its result and symptoms
Lead inactivates many enzymes including ALA dehydrase and ferrochelatase
microcytic sideroblastic anemia with ringed sideroblast
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
What is the result of ferrochelatase failure
how can we diagnose it
Nonenzymatic insertion of Zn2+ to form zinc protoporphyrin
This complex is extremely fluorescent and is easily detected
what are the etiologies of lead poisoning
how can it get diagnosed
Lead paint, Pottery glaze, Batteries
Diagnose by measuring blood lead level
what is the etiology of red wine urine in porphyria
porphyrin”ogen”s are colourless
In the presence of oxygen, they spontaneously oxidize, formirng a conjugated double-bond network in the compounds named porphyr”in” which is colourfoul
what forms of iron we eat, we absorb
binds to transferrin, ferritin, use in heme
we eat Fe3+, absorb Fe2+
ferritin and transferrin Fe3+
heme Fe 2+
How is iron bind transferrin and ferritin
Feroxidase(ceruloplasmin, Cu2+ protein) oxidize Fe2+ to bind with transferrin
Ferritin oxidizes Fe2+ itself
What is Hemosiderin
ferritin precipitation
Hemosiderin binds excess Fe3+ to prevent escape of free Fe3+ into the blood, where is toxic
what is daily need and rate of absorption of iron
Human absorb 1mg/d Iron, 10% of Iron intake will be absorbed > daily need 10mg
what is Hemochromatosis
Prevalence, genetic, symptoms
Autosomal recessive disease, defect in HFE channel
prevalence of 1/200, men >40 years old and in older women
daily intestinal absorption of 2-3 mg of iron
Over 20-30 years
Early symptoms of early fatigability and lethargy
Hemosiderin deposits are found in the liver (cirrhosis), pancreas (Diabetes), skin, and joints (Arthritis)
bilirubin metabolism untill secretion
globin degrade to its aminoacids
Heme to Iron and Carbon monoxide and biliverdin
bilirubin in blood with albumin
Hepatocytes conjugate it with 2 glucuronic acid
secreted into the bile
Conjugation enzyme of bilirubin and its substrate and reslults
UDP glucuronyl transferase
add 2 UDP glucuronate to bilirubin
make bilirubin diglucuronide
bilirubin secretion features
Intestinal bacteria cut off both sugars
glycolysis then NADH
Electrons then put on bilirubin and make urobilinogen
mostly in feces in form of stercobilin
small absorb and in urine in form of urobilin
what is the color of heme, biliverdin, bilirubin
Purple, Green, Yellow-Orange
what is the color of urine in hemolysis
deeper colored due to excessive bilirubin production and urobilinogen in intestine
so it is also increased in urine
etiology of jaundice in newborns
therapy
Massive erythrocyte destruction in 1st days, HbF not respond to 2,3 BPG
UDP-glucuronyl transferase induced only at birth
Phototherapy > Blue light(not UV), Bil absorb light, fragments to water soluble particles
Lab results in alcoholic liver
AST increases more than ALT
