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Flashcards in Kaplan Biochem Ch 4 Deck (100)
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61

Ehlers-Danlos Syndromes represent a collection of defects in the _______
- like Osteogenesis Imperfecta, these syndromes are a result of _____ in which defects in several different genes (loci) can result in similar symptoms

Ehlers-Danlos Syndromes represent a collection of defects in the normal synthesis and processing of collagen
- defect = mutations in collagen genes and lysyl hydroxylase gene
- like Osteogenesis Imperfecta, these syndromes are a result of locus heterogeneity in which defects in several different genes (loci) can result in similar symptoms

62

- EDS type IV, the ____ type, is an autosomal ____ disease caused by mutations in the gene for _____
- Characteristic features include:

- EDS type IV, the vascular type, is an autosomal dominant disease caused by mutations in the gene for type 3 procollagen.
- Characteristic features include:
- thin, translucent skin
- arterial, intestinal or uterine rupture,
- and easy bruising

63

Scurvy is a disease with

Scurvy is a disease with deficient hydroxylation secondary to ascorbate deficiency

64

Major symptoms of Scurvy

petechiae, ecchymoses, loose teeth, bleeding gums, poor wound healing, poor bone development

65

- Osteogenesis imperfecta is a disease resulting in mutations in ______
- major symptoms:

- Osteogenesis imperfecta is a disease resulting in mutations in collagen genes.
- major symptoms: skeletal deformities, fractures, blue sclera

66

Major symptoms of EDS

hyperextensible, fragile skin, hypermobile joints, dislocations, varicose veins, ecchymoses, arterial, intestinal ruptures

67

the ____ signal sequence is used to ensure translation on the RER

the N-terminal hydrophobic signal sequence is used to ensure translation on the RER

68

Menkes Disease results in ____
- cause:
- type of diasese
- specific mutation:

Menkes Disease results in deficient cross-linking secondary to functional copper deficiency
- aka EDS type IX (Kinky hair syndrome)
- X-linked recessive disease
- incidence of 1/100,000 newborns
- mutation in gene ATP7A, which encodes an ATP-dependent copper efflux protein in the intestine

69

_______ is important for directing and enzyme to a lysosome.

Phosphorylation of mannose residues is important for directing and enzyme to a lysosome.

70

Major symptoms of Menkes Disease

depigmented (steely) hair, arterial tortuosity and rupture, cerebral degeneration, osteoporosis, anemia

- aka EDS type IX (Kinky hair syndrome)
- symptoms (in part) due to weak collagen

71

The domains of the IgG molecule are examples of ___ structure

The domains of the IgG molecule are examples of tertiary structure:
- the positioning of 2ndary structures in relation to each other to generate 3D shapes
- Tertiary structure also includes the shape of the protein as a whole (globular, fibrous)

72

- Mutation causing Menkes Disease
- result

- mutation in gene ATP7A, which encodes an ATP-dependent copper efflux protein in the intestine
- Copper can be absorbed into the mucosal cell, but cannot be transported into the bloodstream
- Consequently, an affected individual will have SEVERE copper deficiency and all copper-requiring enzymes will be adversely affected
- Lysyl oxidase requires copper and plays a direct role in collagen formation by catalyzing the cross-linking of collagen fibrils.
- deficiency in the activity of this enzyme and other copper-dependent enzymes would be responsible for symptoms

73

Is Collagen extracellular or intracellular?

Collagen is Extracellular!
- very HY! Found in bones, BM, tendons
- when see hydroxyproline think collagen (= AA unique to collagen)
- collagen is a triple repeat tripeptide (Gly-X-Y) with 3 strands and every 3rd AA is glycine
- Gly-X-Y

74

Examples of N-linked glycoproteins

- blood clotting factors
- immunoglobulins
- receptors
- transporters
- blood groups

75

Synthesis of secretory, membrane, and lysosomal proteins

* this only happens to proteins that leave the cytoplasm. i.e., go to lysosome, go to cell membrane, or are secreted

1. translation begins in cytoplasm on free ribosomes, but after translation of the signal sequence...
2. signal sequence causes ribosomes to attach to ER
3. translation continues on RER
4. During translation, the nascent protein is fed through the membrane of the RER and captured in the lumen.
5. signal peptidase removes the signal sequence (bc its only function is entrance to ER lumen)
- then the protein passes into the Golgi for further modification and sorting. In transit through the ER and golgi, the proteins acquire oligosaccharide side chains commonly attached at SERINE and THREONINE residues (if O-linked) or at ASPARAGINE residues (if N-linked)
6. N-linked glycosylation (in ER) requires participation of a special lipid called dolichol phosphate
7. proper folding is required in ER for transfer of protein to Golgi
8. phosphorylation of mannose by phosphotransferase signals to lysosome
9. from lysosome proteins go to cell membrane for secretion (or to be part of membrane)

76

- O-linked glycosylation
- examples of things that are O-glycosylated

- Occurs in the golgi
- i.e. serine or threonine
- Examples: cOllagen is O-glycosylated
- proteoclycans, hyaluronic acid (lubricants), chrondroitin, mucins

77

Lysyl Oxidase

Lysyl oxidase requires copper and plays a direct role in collagen formation by catalyzing the cross-linking of collagen fibrils.

78

collagen is a triple repeat tripeptide with 3 strands and every ___ AA is ____

collagen is a triple repeat tripeptide with 3 strands and every 3rd AA is glycine

79

Examples of proteins that are NOT glycosylated

- albumin
- insulin
- glucagon

80

This sequence is found on proteins that are destined to be secreted (ex insulin), placed in the cell membrane (i.e. Na+-K+ ATPase), or ultimately directed to the lysosome (i.e. sphingomyelinase)

the N-Terminal hydrophobic signal sequence

81

- 4mo who fails to grow and appears mentally retarded, with kinky, hypopigmented hair. What else do you expect to see on further examination?
- diagnosis?
- gene mutated?
- result?

- Expect to see elongation and tortuosity of the major arteries on arteriogram
- additional tests may reveal bladder diverticula and subdural hematomas
- blood test will show low serum ceruloplasmin and only 10% normal copper levels
- Diagnosis: Menkes Disease
- disease caused by mutations in the gene ATP7A, which encodes the ATP-dependent copper efflux protein in the intestine.
- result: Severe copper deficiency bc copper can be absorbed into the mucosal cell but can't be transported into the bloodstream.

82

in O-linked glycosylation the oligosaccharide side chains are attached at ____ and ____ residues

In transit through the ER and golgi, the proteins acquire oligosaccharide side chains commonly attached at SERINE and THREONINE residues (if O-linked)

83

Lysosomal enzymes are glycosylated and modified in a characteristic way. Most importantly, when they arrive in the Golgi, specific _____ residues in their oligosaccharide chains are _________

Lysosomal enzymes are glycosylated and modified in a characteristic way. Most importantly, when they arrive in the Golgi, specific MANNOSE residues in their oligosaccharide chains are PHOSPHORYLATED by N-ACETYLGLUCOSAMINE-1 PHOSPHOTRANSFERASE
- this phosphorylation is the critical event that removes them from the secretion pathway and direct them to lysosomes

84

Genetic defects affecting the phosphorylation of lysosomal enzymes produces I-cell disease in which ___

Genetic defects affecting the phosphorylation of lysosomal enzymes produces I-cell disease in which lysosomal enzymes are released into the extracellular space and inclusion bodies accumulate in the cell, compromising its function

85

Major function of lysosomes and how do they do that?

- to digest materials that the cell has ingested by endocytosis
- lysosomes contain multiple enzymes that collectively, digest carbohydrates (glycosylases), lipids (lipases), and proteins (proteases)
- when a lysosomal enzyme is missing the undigested substance accumulates in the cell and can lead to serious consequences

86

Lysosomes are especially prominent in which cells

lysosomes are especially prominent in neutrophils and macrophages

87

- In N-linked glycosylation proteins acquire oligosaccharide side chains commonly attached at _____ residues
- N-linked glycosylation requires participation of ____

- In N-linked glycosylation proteins acquire oligosaccharide side chains commonly attached at ASPARAGINE residues
- N-linked glycosylation (in ER) requires participation of a special lipid called dolichol phosphate

88

Major symptoms of I-cell disease

- coarse facial features, gingival hyperplasia, macroglossia
- craniofacial abnormalities, joint immobility, clubfoot, claw-hand, scoliosis
- psychomotor retardation, growth retardation
- cardiorespiratory failure, death in first decade
- bone fracture and deformities (i.e. can be born with dislocated hips, etc)
- mitral valve defect (heart murmur)
- secretion of active lysosomal enzymes into blood and extracellular fluid
- hepatosplenomegaly
- suffer from repeated URT infections

- examination of fibroblasts from skin biopsy shows presence of numerous intracellular inclusions (can see large lysosomes on ECM)
- biochemical analysis shows decreased levels of lysosomal hydrolase beta-glucuronidase within the fibroblasts, but elevated levels of this enzyme within the culture medium

89

glycosylation

addition of oligosaccharide as proteins pass through the ER and Golgi apparatus

90

proteolysis

cleavage of peptide bonds to remodel proteins and activate them
- ie proinsulin, trypsinogen, prothrombin