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Biochemistry Exam 2 > Lecture 16 : Metabolic Disease and the Maxiofacial Complex > Flashcards

Lecture 16 : Metabolic Disease and the Maxiofacial Complex Flashcards

1
Q

What is a metabolic disease?

A

A metabolic disease is any disruption of the ability of the cell to perform critical biochemical reactions involved in the process of converting food to energy on a cellular level (i.e., metabolism).

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2
Q

What can metabolic disease involve?

A

Can involve the processing, transport or absorption of proteins (amino acids), carbohydrates (sugars and starches), or lipids (fatty acids).

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3
Q

How do people get Metabolic Diseases?

A

They’re typically heritable. Not only metabolic diseases have a genetic basis, but a lo

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4
Q

What is used to help regulate pathway activities?

A

Feeback Mechanisms, >>Level of robustness<

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5
Q

How do Metabolic Disease appear variable in presentation?

A

In Many cases, Metabolic diseases only appear when the body is stressed.

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6
Q

What do many metabolic diseases affect?

A

Bone (and cartilage)

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7
Q

At what stages of life can metabolism have an impact?

A

All stages, Infancy, reflecting an impact on the embryo/fetus Adolescence Adult B/c it is an interplay b/w genetics and environmental stressors that actually can create metabolic disease

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8
Q

Flow Chart of Factors to impact the development of metabolic bone disease

A
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9
Q

What the purpose of newborn screening in regards to metabolic disease?

A

Allows for early treatment or dietary intervention to prevent/manage/delay symptoms.

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10
Q

When is Prenatal screening done?

A

In severe cases

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11
Q

What are some things screened for in newborns (metabolic diseases)?

A

Phenylketonuria (PKU), hypothyroidism, galactosemia, sickle cell disease, cystic fibrosis (CF).

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12
Q

What is glycosylation?

A

process by which sugar ‘trees’ (glycans) are created, altered and chemically attached to certain proteins or fats (lipids).

process by which sugars (glycans) added on to certain proteins or fats(lipids)

one of the major forms of post-translational modifications

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13
Q

What are congenital disorders of glycosylation (CDG) characterised by?

A

Variable dysmorphic features

(Prominent forehead, dysplastic ears and large ear lobules, thin upper lip, long philtrum, prominent jaw (develops with age as mandible can start as retrognathic), narrow/short palpebral fissures, prominent nose and anteverted nares, high-arched palate)

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14
Q

What are the different types of glycosylation?

A

Simple monosaccharide modifications of nuclear transcription factors

Complex branched polysaccharides (GAGs) on cell surface receptors

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15
Q

What does protein glycosylation impact?

A

Protein glycosylation impacts protein folding in ER, distribution in the cell, stability and activity.

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16
Q

Glycosylation =?

A

Polysaccharide modification of a protein

Large variation in pattern

(adding one or more sugar moieties)

I.e. mannose, fructose, galactose, glucose,

added on and linked to each other and can form large and diverse chains that are attached to proteins

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17
Q

How do patterns of glycosylation vary?

A

They are cell type-specific

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18
Q

Protein glycosylation is complex because…

A

of the differential expression of the genes encoding the respective enzymes

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19
Q

What’s the difference b/w the two major types of glycosylation?

A

The way they’re attached to the protein

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20
Q

What is N-linked Glycosylation

A

When you’re attaching sugar moieties to an asparagine residue on a protein

Carried out by a particular enzyme

▸refers to amide bond (beta-conformation) formed between GlcNAc (acetylglucosamine) and the amino acid, Asparagine (Asn:N), in a protein. Occurs within the endoplasmic reticulum (ER).

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21
Q

What is O-linked Glycosylation?

A

Refers to Carbs bound to a protein backbone using Hydroxyl residue on Serine, Threonine, and Tyrosine

OH facilitates that attachment

Occurs mostly in ER and Golgi

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22
Q

What is the slight difference between N-linked and O-linked Glycosylation?

A

N-linked is almost all done in the ER whereas the O-linked Glycosylation goes both in the ER, Golgi, and also to a certain degree in the cytoplasm.

19:00

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23
Q

What will happen if there are mutations in any of the 12 genes responsible for O-linked glycosylation?

A

They will all lead to a similar phenotype.

Muscular dystrophy due to the importance of the O-Glycosylation for the anchoring function of dystroglycan in major muscle proteins.

Result is muscle disruption

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24
Q

What happens to mutations in N-:inked Glycosylation?

A

Results in a variety of different things,

they DO NOT GIVE THE SAME PHENOTYPE,

they group in clusters

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25
Q

What do mutations in N-linked glycosylation affect?

A

Depends on the defective enzyme in the process of assembly, which is why it was mentioned that mutations in N-linked Glycosylation are clustered.

Modifications that are going on have very specific functions in certain tissues during development.

Often seeing that phenotype that the individual has can often give you an idea roughly where the mutation might not be effected.

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26
Q

What are some Clincal Testings for CDG?

A

Simple Blood Test - analyzes glycosylation status of transferrin (a circulating glycoprotein essential for iron transport)

Electrospray ionization-mass spectrometry can also be used to detect abnormal transferrin - more specific (subtype detection).

Enzyme activity assay for some subtypes.

Molecular genetic testing is needed for confirmation.

27
Q

What does a simple blood test do?

A

analyze the glycosylation status of transferrin (a circulating glycoprotein essential for iron transport).

28
Q

What does electrospray ionization-mass spec do?

A

can be used to detect abnormal transferrin - more specific (subtype detection).

29
Q

What would be needed for confirmation?

A

Genetic Testing

30
Q

What is enzyme activity assay used for?

A

It’s used for some subtypes

31
Q

What does Isoelectric Focusing (IEF) do?

A

separate molecules such as proteins or enzymes based upon their electrical charge

different bands represent different modifications,

more sugar residues attached to it means the charge changes so it migrates differently so you see the complex, indicative that there’s a change in the moieties that have been added to the protein

32
Q

What is Glycosaminoglycans (GAGs)?

A

A family of highly sulfated,

complex-linear polysaccharides as opposed to multichain glycosylation which is characteristic of N-linked and O-linked Glycosylation,

Gags have a variety of biological roles:

33
Q

What are the four main roles of Glycosaminoglycans (GAGs)?

A

‣Heparin/heparan sulfate

‣Chondroitin sulfate/dermatan sulfate

‣Keratan sulfate

‣Hyaluronan

34
Q

Which GAGs primarily affect bone and cartilage?

A

Chondroitin sulfates/dermatan sulfates

29:20

35
Q

What is the primary role of GAGs?

A

Hydrating the environment around cells,

to give them some of their tensile strength and elasticity and resist compressive forces both during development and adult life

36
Q

How long are GAGs?

A

Up to 80 sugars linked to protein (proteoglycan) in the ER and Golgi

37
Q

Where are GAGs subsequently sulfated?

A

In the Golgi

38
Q

What does sulfating GAGs do and where does this happen?

A

Sulfating Gags further modulates properties of the protein, it is done in the Golgi.

39
Q

Blueline is protein, long chains are attached to multi-points on protein, Hyaluronan is one of the exceptions

Nonsulfated, not protein attached, free polysaccharide synthesized at the plasma membrane

A
40
Q

What do GAGs do?

A

They’re like an extracellular gel,

  • Provide Tensile Strength and Elasticity
  • Resists Compressive Forces
41
Q

What are some functions of Glycosaminoglycans (GAGs)

A

In the Extracellular Matrix of the cell,

Diverse structural properties are critical for providing/modulating the availability of growth factors, particularly how cells respond to growth factors

B/c any changes to hydration levels or presence of these in ECM or the level of expression of the growth factors and under certain conditions can all be modulated intracellularly by these factors.

42
Q

What are some functions of Glycosaminoglycans (GAGs)

A

▸The diverse structural properties are critical for modulating receptor/ligand binding, affecting cell function & tissue morphogenesis.

Have major role in both Tissue Morphogenesis during development

BUT ALSO IN

Maintaining tissues in Adult life as well

43
Q

What are Mucopolysaccharidoses (MPS)

A

MPS are diseases are a result of disruption to the breakdown of GAGs polysaccharide chains

44
Q

What is Mucopolysaccharidoses characterized by?

A

Lysosomal storage of GAGs

45
Q

What does progressive accumulation of GAGs result in?

A

affects the cell’s ability to respond, so as a result:…

  • Skeletal Defomorities
  • Poor Joint Mobility
  • Severe Growth Deficit
  • Coarse Facial Features
  • Enlarged Organs
46
Q

What are MPS I (Hurler Syndroe) & MPS II (Hunter Syndrome) characterized by?

A

Gingival hyperplasia, delayed tooth eruption, malocclusion, mandibular dysplasia, radiolucent lesions in the jaws, and condylar defects.

47
Q

MPS 1 and 6

Mistake mad in the slides 34:00

A

? Mistake made in the MPS 1 and 6? should they be switched around?

48
Q

What is Smith-Lemli-Ooitz Syndome (SLOS)

A
  • Disorder of cholesterol metabolism
  • Caused by mutation in the DHCR7 gene
    • Encodes Dehydrocholesterol delta reductase (the final enzymatic step in the cholesterol biosynthesis pathway, associated with a bunch of abnormalities)
  • Elevated cholesterol precursors, decreased cholesterol

Abnormalities associated with mutation in DHCR7 gene:

▸Multiple anomalies (cardiac, urogenital, digit, renal, pulmonary), dysmorphic face, growth deficiency, mental retardation, including autism, epilepsy, aggression, self-mutilation

49
Q

When does SLOS occur?

A

Because the SLOS mutation occurs in the last step in the pathway for Cholesterol, you’ll get a build-up of precursors.

The build-up of these precursors causes problems because they can’t progress, they won’t be able to complete their functions in the cell and embryo

Important to know that just because there’s a deficiency of one thing, that doesn’t mean that is necessarily the cause for the buildup of precursors in the pathway

50
Q

What are the major functions of Cholesterol?

A
  • Cell Membranes
  • Myelin (axonal)
  • Bile Acids
  • Steroid Hormones
  • SHH Signaling
    • Sonic Hedge Hog
      • Major regulator of Embryogenesis
      • Cholesterol is a major component to optimize signalling in that pathway, which is why it has such a major role in early development.
51
Q

Cholesterol Molecule

A
52
Q

What does SHH play a major role in?

A

SHH plays a major regulator of Embryogenesis

53
Q

What happens to patients with SLOS with a cholesterol level ≤0.35 mmol/L?

A

They died early b/c:

‣electrolyte abnormalities [eg. hyperkalemia, hyponatremia, hypocalcemia], necrotizing enterocolitis, sepsis-like episodes, midline defects including branchial and cardiac defects.

54
Q

SLOS Patients with cholesterol levels ≥1.7 mmol/L had milder features and were diagnosed at 9 months to 25 years of age:

A

All had intellectual disability.

55
Q

What do ALL SLOS patients have in common?

A

crowded teeth, widely spaced incisors, oligodontia, polydontia, premature tooth eruption, enamel hypoplasia, bifid uvula, broad alveolar ridges, bifid tongue, and Pierre-Robin sequence (glossoptosis, retrognathia and cleft palate)

56
Q

What is Holoprosencephaly (HPE) spectrum?

A

HPE is commonly associated with defects in the Sonic HedgeHog (SHH) pathway, which is known to be regulated by cholesterol.

57
Q

What is SHH Signaling a major Pathway for?

A

SHH Signalling is a major pathway for coordinating embryonic morphogenesis and patterning, particularly the brain and the midline of the craniofacial complex.

58
Q

What is SHH?

A

SHH is a secreted ligand

59
Q

What are the two SHH co-receptors?

A
  • Patched (PTCH - represses)
  • &
  • Smoothened (SMO - activates)
60
Q

SHH is a morphogen, what does that mean?

A

It’s created by cells and it can, as a morphogen, be transported across multiple cell distances to induce change in cells at a distance.

61
Q

How does SHH signalling occur?

A
  • SHH signalling occurs through primary cilia (cilium)
    • ( a cytoskeletal membrane structure that protrudes from the cell)
    • Present on osteoblasts and odontoblasts
62
Q

PTCH1 receptor????

A
63
Q

True or False,

Metabolic Diseases can have significant impact on the maxillofacial complex at all ages (embryonic and postnatal)

A

True

Biochemistry Exam 2 (7 decks)

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