Biochemestry

Question 1

Particular feature of arginase deficiency that differentiate from other urea cycle disorders.

Answer 1

Mild or NO hyperammonemia

Question 2

Functions of tetrahydrobiopterin (BH4)

Answer 2

Cofactor of the most important hydroxylases:
- phenylalanine hydroxylase (tyrosine synthesis, PKU if deficient this enzyme or dihydrobiopterin reductase→synthesis of BH4 [cofactor of phe hydroxylase►malignant PKU→↓↓BH4])
- tyrosine hydroxylase (cathecolamine [from DOPA] synthesis )
- tryptophan hydroxylase (5HT synthesis)
Also for nitric oxide synthase

Question 3

Ashkenazi Jews show high incidence of what type of metabolic diseases?

Answer 3

Tay-sachs, Niemann-pick, some forms of Gaucher. (Shingolipidoses)

Question 4

How do you differentiate or identify cori disease from other glycogen diseases, which enzyme is deficient?

Answer 4

• Involve muscle (hypotonia, weakness) and liver (hepatomegaly, fibrosis) ▶️ different of Hers and Von Gierke (also liver involve)
• debranching enzyme deficiency
• hypoglycemia, ketoacidosis, abnormal short outer chain inside hepatocytes

Question 5

How is the B-oxidation of fatty acids in a high-carbohydrate, high-protein diet? How does that state occur?

Answer 5

• Inhibited
• Malonyl-CoA▶️❌carnitine acyltransferase▶️ fatty acids can not go to the mitochondrial matrix ▶️ no B-oxidation.
• Well-fed state ▶️ ⬆️ ATP ▶️ ❌ isocitrate deshydrogenase ▶️ ⬆️ citrate in mitochondria ▶️(citrate shuttle) cytosol ▶️(ATP citrate lyase) Acetyl-CoA ▶️ Acetyl-CoA carboxylase ➕ by citrate, insulin ▶️ malonyl-CoA►(Fatty acid synthase) Fatty acids

Question 6

Signs and symptoms of Homocystinuria. 50% of patients respond to which supplementation? Other measures of treatment.

Answer 6

• Marphanoid habitus, ectopia lentis, atherosclerosis, thromboembolic occlusions (MI, stroke), intellectual dissability, osteoporosis, kyphosis.
• High doses of pyridoxine (vitamin B6)
• Restriction methionine if cystathionine synthase deficiency

Question 7

What is the Zellweger syndrome?

Answer 7

• Deficient or absent peroxisome (member of family Leukodistrophies) ▶️ Infants unable to properly form myelin
• Hypotonia, seizures, hepatomegaly, mental retardation, early death

*More severe of 3, others: Refsum disease, Neonatal adrenoleukodistrophy (NALD)

Question 8

Cause and mechanism of Refsum disease.

Answer 8

Defect peroxisomal alpha-oxidation ▶️ accumulation of pythanic acid ▶️ neurological disturbances

Question 9

The first enzyme of the gluconeogenesis converts pyruvate in which component and who regulates that enzyme?

Answer 9

Pyruvate (Pyruvate carboxylase [biotin]) ▶️ Oxaloacetate (in mitocondria)
⬆️ Acetyl-CoA ▶️ ➕ Pyruvate carboxylase ⏩ gluconeogenesis

*⬇️ Acetyl-CoA ▶️ ➕ Pyruvate deshydrogenase ⏩ glycolysis

Question 10

Markers of Vitamin B12 deficiency

Answer 10

⬆️ Mehylmalonic acid, ⬆️ homocysteine

- cofactor for methylmalonyl-CoA mutase, methyonine synthase

Question 11

How do you treat an acute intermittent porphyria attack and why? Cause of the disease and what can precipitate the attacks?

Answer 11

• Hemin and Glucose ▶️ 🚫 dALA synthase ▶️ ⬇️ dALA
• Deficiency of Porphobilinogen deaminase (inherited) ▶️ ⬆️ Porphobilinogen (PBG)
• Induction of dALA synthase ▶️ ⬆️ Aminiolevulinate (dALA) [phenobarbital, griseofulvin, phenytoin, alcohol, progesterone - puberty, low-calorie diet]

Question 12

Which amino acids are useful to treat Pyruvate dehydrogenase deficiency, why? Other measures to treat it?

Answer 12

Lysine or Leucine ▶️ exclusively ketogenic

*Tx: ketone bodies as fuel in placed of Glucose ⏭ ketogenic diet ▶️ high fat, low carb, moderate protein; ketogenic AA. Because:
Glucose ▶️ pyruvate ▶️ ⬆️ lactate ▶️ lactic acidosis

Question 13

Causes of secondary lactase deficiency

Answer 13

• Infections→ex common: Giardiasis
• Inflammation→ex: celiac disease

*Epithelial destruction and replace by immature cells with low lactase

Question 14

Which enzymes use as cofactor vitamin B12, and for this reason which components build up in a vitamin B12 deficiency?

Answer 14

• Methionine synthase (⬆️ Homocysteine)

- Methylmalonyl CoA mutase (⬆️ Methylmalonic acid)

Question 14

Cause and laboratory findings in a Methylmalonic acidemia. Clinical presentation.

Answer 14

• Methylmalonyl CoA mutase deficiency (AR) ▶️ ⬆️ Methylmalonic acid, propionic acid ▶️ metabolic acidosis ▶️ hyperammonemia, hypoglycemia ▶️ ⬆️ ketone bodies (⬆️ anion gap)
• Lethargy, vomiting, hypotonia, tachypnea

Question 16

In what reaction and by which enzyme of the cycle of krebs is produced the cofactor needed to form phosphoenolpyruvate from oxaolacetate during gluconeogenesis?

Answer 16

Succinyl-CoA ⏩ succinate [succinyl-CoA synthetase or succinate thiokinase] ⤴️ GTP ▶️ needed by phosphoenolpyruvate carboxykinase [oxaloacetate ▶️ PEP]

Question 17

During starvation what hormone mediates the increase of substrates for gluconeogenesis and ketogenesis?

Answer 17

• Hormone-sensitive lipase (HSL)
• Stress hormones (cortisol, Epi, glucagon)►Gs protein coupled receptor in adipocytes→phosphorylate (PKA)→(+)HSL→lipolysis→release of free fatty acids and glycerol taken by liver
• FFA→acetyl-CoA→ketone bodies or TCA (energy for gluconeogenesis)
• Glycerol→gluconeogenesis

Question 18

Clinical presentation of Hartnup disease. What vitamin deficiency cause them and why?

Answer 18

• Photosensitivity, pellagra-like symptoms (diarrhea, dementia, dermatitis), ataxia→wax and waine during disease, aminoaciduria (neutral aa)→differentiates from other causes of aminoaciduria (Fanconi syndrome)
• Intestinal and renal absorption of tryptophan (essential aa precursor of nicotinic acid, 5HT, melatonin) is defective→Niacin (B3) deficiency

Question 19

Causes of vitamin B3 (Niacin) deficiency.

*What is the disease?

Answer 19

• Hartnup disease→↓intestinal and renal absorption of some neutral amino acids, including tryptophan (precursor of niacin)
• Vitamin B6 (pyridoxine) deficiency→ex, Isoniazid►B6 needed to synthesis of niacin from Trp
• Malignant carcinoid syndrome→↑metabolism of Trp
• Dietary→↓intake Trp, Lysine, ↑intake leucine

*Pellagra

Question 20

Most common enzymes deficiencies of the B-oxidation and clinical presentation

Answer 20

• Acyl-coA dehydrogenase deficiency▶️most common⏩hypoketotic hypoglycemia after fasting (⬇️⬇️acetoacetate in blood)
• Primary carnitine deficiency▶️fatty acids not transported to mitochondria⏩muscle weakness, cardiomyopathy, ⬆️muscle triglycerides, hypoketotic hypoglycemia

Question 21

Causes of galactosemia

Answer 21

• GALT deficiency
• GALK deficiency
• UDP-galactose-4 epimerase

Question 22

Cause and consequence of glactose-1-phosphate accumulation

Answer 22

• Galactose-1-phosphate uridyl transferase (GALT) deficiency
• Toxic accumulation→liver dysfunction►transaminitis, hyperbilirrubinemia, hypoglycemia; renal dysfunction►hyperchloremic metabolic acidosis, aminoaciduria; predisposition to E. coli sepsis; cataract►galactitiol accumulation in lens

Question 23

Treatment of GALT deficiency

Answer 23

Replace breast milk by soy milk (glucose+fructose)

Question 24

Effect of ethanol on gluconeogenesis and why does it occur?

Answer 24

Ethanol▶️⬆️NADH, ⬇️NAD (alcohol dehydrogenase and aldehyde dehydrogenase reduces NAD to NADH)▶️NAD is require for gluconeogenesis:

• ❌Lactate▶️pyruvate (intermediate of gluconeogenesis)
• ❌Malate▶️Oxaloacetate (intermediate of gluconeogenesis)

Question 25

What is produced during the oxidative irreversible stage of pentose phosphate pathway and its functions?

Answer 25

NADPH (main source)▶️cholesterol (steroids) and fatty acid synthesis, glutathione antioxidant mechanism

Question 26

Important products of nonoxidant (reversible) stage of pentose phosphate pathway and its functions.

Answer 26

• Ribose 5-phosphate▶️nucleic acid synthesis

- Fructose 6-phosphate (others glucolytic intermediates)▶️glycolysis

Question 27

What is the useful of urine copper reduction test?

Answer 27

Detection of reducing sugars in urine (galactose, fructose, glucose)▶️nonspecific for inborn errors of carbohydrate metabolism

Question 28

Which mechanism do TNF-alpha, glucagon, catecholamines and corticoids use to induce insulin resistance?

Answer 28

➕Serine kinases▶️phosphorylation at serine residues on beta subunits of insulin receptor (IR) and on insulin receptor substrate (IRS)→🚫normal tyrosine phosphorylation of them▶️⬇️insulin downstream signaling

Question 29

From lipolysis which substrate may be used to produce glucose (gluconeogenesis) and what enzyme initially allow that?

Answer 29

Triglycerides→Glycerol+fatty acids→glycerol to liver (glycerol kinase)→glycerol 3-phosphate (glycerol 3-phosphate dehydrogenase)→DHAP►glucose

Question 30

Which tissues cannot use ketone bodies as source of energy?

Answer 30

• Erythrocytes▶️lack mytochondria
• Liver▶️lack succinyl CoA acetoacetate CoA transferase (thiophorase) (acetoacetate▶️acetoacetyl Coa)

*Skeletal muscle, cardiac muscle (both primarily consumed KB to preserve Glc for brain), brain (prolonged starvation), kidney

Question 31

How is activated the phosphorylase kinase at skeletal muscle and liver and what is the result of it?

Answer 31

• Liver: Epinephrine, glucagon▶Gs protein-coupled receptor▶⬆cAMP▶➕PKA▶➕phosphosrylase kinase (PK)➡glycogenolysis▶maintain blood glucose levels during fasting state
• Skeletal muscle: Ca release from sarcoplasmic reticulum▶➕PK➡glycogenolysis▶energy necessary for anaerobic muscle contraction (synchronization with contraction)

Question 32

Which feature of elastin explains its rubber like properties?

Answer 32

Lysyl oxidase (requires copper)→oxidatively deaminates lysine residues to tropoelastin→formation of demosine cross-links between neighboring polypeptides

Question 33

What supplementation do you use to treat maple syrup disease and why?

Answer 33

Thiamine→one of the cofactors of branched-chain α-ketoacid dehydrogenase
*Also dietary restriction Leucine, Isoleucine, Valine

Question 34

What have in common branched-chain α-ketoacid dehydrogenase, pyruvate dehydrogenase and α-ketoglutarate dehydrogenase?

Answer 34

Need same cofactors:
Thiamine, Lipoate, Coenzyme A, FAD, NAD
“Tending Loving Care For Nancy”

Question 35

What is the most abundant amino acid in collagen? What is the function of the other common amino acids?

Answer 35

• Glycine→most common
• Proline→essential for alpha-helix formation
• Hydroxylysine→need for cross-linking

Question 36

What disease is caused by defect in phosphorylation of manose in a newborn with coarse facial features, skeletal abnormalities (congenital dislocation of hip), psycomotor abnormalities? Pathogenesis.

Answer 36

• I-cell disease (inclusion cell disease/mucolipidosis type II)
• Defect in N-acetylglucosaminyl-1-phosphotransferase→failure of the Golgi to phosphorylate mannose residues (↓mannose-6-phosphate) on glycoproteins→proteins are secreted
  extracellularly rather than delivered to lysosomes

Question 37

What sphingolipid disease has both peripheral neuropathy and progressive neurodegeneration? what other feature depict that disorder?. Mention enzyme deficiency and substrate that build up.

Answer 37

• Krabbe disease→↓Galatocerebrosidase→↑Galactocerebroside

- Optic atrophy, globoid cells

Question 38

Treatment for orotic aciduria

Answer 38

Uiridine phosphate supplementation→bypass mutated enzyme (UMP synthase)

Question 39

Cause of alkaptonuria. Clinical presentation.

Answer 39

Deficiency Homogentisate oxidase (or deoxygenase)→↑↑Hogentisic acid (Tyrosine metabolism to fumarate→TCA)

• Ochronosis→bluish-black connective tissue, ear cartilage, sclera
• Urine turns black after prolongued exposure to air
• Debilitating arthralgias→Ochronotic arthropathy

Question 40

Extracellular processing of collagen

Answer 40

• N and C terminal cleaving by procollagen peptidases→procollagen►Tropocollagen (less soluble)
• Tropocollagen monomers self-assemble into collagen fibrils
• Lysyl oxidase→covalent crosslinks between collagen fibrils►strong collagen fibers

Question 41

What is the role of the IkB in the activation of NF-kB and the pathway by which it can occur?

Answer 41

• IkB normally bind and mantain in cytoplasm the NF-kB►phosphorylation of IkB (target to proteasome) release NF-kB→nucleus as a transcription factor
• Cytokines (IL-1) and TNF-alpha receptors pathway→(+) IKK comples→phosphorylation of IkB