Amino Acid and Protein Metabolism (Week 4--Howard)

Question 1

How do we make amino acids?

Answer 1

Major source of AAs is diet

Also can make AAs ourselves from intermediates from glycolysis and TCA cycle

We also make AAs from breaking down our own body proteins

Question 2

Essential amino acids

Answer 2

We don’t make them, so need to consume them in the diet

Important examples: phenylalanine, arginine, methionine

(Mnemonic: PVT TIM HALL)

Question 3

How do we synthesize most amino acids (non-essential)?

Answer 3

Transamination of respective alpha-keto acids from intermediates of glycolysis and TCA using vitamin B6 as a cofactor

Question 4

Nitrogen balance

Answer 4

Intake nitrogen = excretion nitrogen (as urea or ammonium)

Occurs in normal healthy adult

Question 5

Positive vs. negative nitrogen balance

Answer 5

Positive nitrogen balance: intake > excretion (growth, pregnancy, tissue repair)

Negative nitrogen balance: excretion > intake (starvation, malnutrition, illnesses, surgery, burns)

Question 6

Why do you have increased nitrogen excretion when you have a major burn?

Answer 6

Get increased cytokines, which increase protein breakdown (prob because of increased synthesis of ubiquitin/proteasome pathway) and this causes muscle breakdown/atrophy

Question 7

What can happen to the carbon skeleton of amino acids?

Answer 7

Can be converted to pyruvate or a TCA intermediate that can be converted to glucose (glucogenic)

Can be converted to acetyl CoA or acetoacetate that can be converted to ketone bodies (ketogenic)

Some AAs are both glucogenic and ketogenic

Note: this doesn’t make sense because seems like if you can get to acetylCoA, you can eventually make glucose so everything should be glucogenic…just memorize this anyway!!

Question 8

Protein Energy Malnutrition (PEM)

Answer 8

Deficiency of protein and energy-producing nutrients, particularly affecting children

Kwashiorkor: inadequate intake of protein; edema

Marasmus: inadequate intake of calories; no edema

Marasmic kwashiorkor: features of both

Note: rare to have deficiency in protein but not calories and vice versa!

Question 9

Kwashiorkor (edematous protein energy malnutrition)

Answer 9

Inadequate intake of protein, get edema

Lethargy, apathy, irritability, inadequate growth, lack of stamina, hypotonia, vomiting/diarrhea, edema due to hypoalbuminemia, dermatitis (darkening or depigmentation of skin), sparse/thin hair, reddening/graying of dark hair, stupor, coma, death

Question 10

Marasmus (non-edematous protein energy malnutrition)

Answer 10

Inadequate intake of calories; no edema

Failure to gain weight, irritability, weight loss, listlessness, loss of skin turgor, wrinkly skin, loss of fat, distended or flat abdomen, face shrunken/shriveled, muscle atrophy and hypotonia

Question 11

Hereditary disorders of amino acid metabolism

Answer 11

Many of these diseases result from mutation in gene encoding an enzyme involved in synthesis or catabolism (breakdown to other substrates used in metabolism) of amino acids

Ex: PKU, Alkaptonuria, Maple Syrup Disease

Question 12

Phenylketonuria (PKU)

Answer 12

Phenylalanine hydroxylase (PAH) is defective enzyme

PAH uses BH4 cofactor to convert phenylalanine –> tyrosine

Sometimes, PKU caused by deficiency of BH4 (biopterin) synthesis or reduction of BH2 back to BH4 by dihydropteridine reductase (rare though)

Autosomal recessive, 400 possible mutations of PAH, 1 out of 15,000 births

High blood phenylalanine, phenylketones in urine, mental retardation (brain normally doesn’t contain phenylalanine hydroxylase)

Normal at birth, then micorcephaly, mental retardation, epilepsy, then motor dysfunction in 2nd/3rd decade if untreated

Question 13

Non-PKU hyperphenylalaninemia

Answer 13

Partial PAH enzyme deficiency

Moderately increased blood level phenylalanine but no phenyl ketones

Mental retardation may or may not develop

1 out of 50,000 births

Question 14

What could be brain pathology of PKU?

Answer 14

Not certain, but too much phenylalanine in blood could competitively inhibit transport of other AAs into brain –> if other AAs can’t get into brain, can’t synthesize certain proteins and NTs

If PKU due to BH4 deficiency, can’t synthesize NE, DA, 5HT because need BH4 to make these

Question 15

Screening and treatment for PKU

Answer 15

Screen all infants using just drop of blood and mass spectrometry within 4 hours of birth

Treat with diet low in phenylalanine (need some because essential AA) right away and until at least 12, or for rest of life

If due to BH4 (biopterin) deficiency, then biopterin added to diet (and DA and 5HT)

Question 16

Maternal PKU

Answer 16

Female with PKU properly treated and have children after they’ve resumed diet containing phenylalanine

Mother is fine, but if conceive baby during diet of phenylalanine, baby can have growth retardation, microcephaly, congenital heart disease, developmental disorders

To avoid damage to fetus, mother must go back on low-phenylalanine diet before conception

Question 17

Alkaptonuria

Answer 17

Autosomal recessive defect of homogentisate oxidase

Excrete homogentisic acid (alcapton) in urine which makes urine dark (upon standing), get arthritis of large joints (knee, spine, hip) later in life

No effective treatment

Question 18

Maple Syrup Urine Disease

Answer 18

Defect in branched-chain keto acid dehydrogenase (catalyzes oxidation of branched-chain alpha ketoacids derived from leucine, isoleucine, valine)

Autosomal recessive, 1 out of 200,000

Get maple syrup-like odor of urine, sweat, stool, saliva, earwax b/c of excretion of branched chain ketoacids, nonspecific symptoms in first weeks of life (difficulty feeding, lislessness, occasional vomiting), and later CNS toxicity (hypotonia, seizures, coma, death)

Can get metabolic acidosis due to accumulation of branched chain ketoacids

Pathogenesis could be that accumulation of leucine inhibits entry of other AAs into brain (similar to PKU)

Question 19

Treatment for maple syrup urine disease

Answer 19

Diet low in leucine, isoleucine, valine

Dialysis if acidosis is very severe