metals in disease Flashcards
(128 cards)
1
Q
why must the concentration of each metal be just right?
A
can cause mismetal binding at site for other metals
2
Q
examples of where iron is used in the body?
A
iron sulphur clusters, cytochromes, haemoglobin and mono/di nuclear ion sites
3
Q
difference between cytochromes and haemoglobin?
A
cytochromes are used in electron transfer whereas haemoglobin is for gas binding. cytochromes also have 6 bonds where as haemoglobin has 5 to hold the gas.
4
Q
what are the two states iron exists in the body ?
A
fe2 and fe3 - losses and electron to go form 3 to 2
5
Q
examples of dinuclear ion sites
A
ribonuclotide reductase
6
Q
example of mono ion site
A
iron oxygenases
7
Q
where are iron sulphur clusters made?
A
in the mitochondria
8
Q
where does the inorganic iron come from ?
A
cysteine
9
Q
what does frataxin do ?
A
donates the iron to be used in isc
10
Q
where is heme made?
A
in the mitochondria and cytosol
11
Q
what does FECH stand for?
A
ferrochelatase
12
Q
what does FECH do ?
A
catalysis of the final step in binding iron in heme
13
Q
which metal binds with heme when iron is low?
A
zinc
14
Q
what happens if there is too much iron?
A
mis metalation and drives dangerous reactions - fenton
15
Q
what does SOD stand for?
A
superoxide dismutase
16
Q
what does SOD do ?
A
catalysis of 202 +h2-> h2o2 +o2 , produces hydroxide which is safer than the superoxygen radical at the start.
17
Q
what does the fenton reaction do ?
A
make very dangerous hydroxyl radicals
Fe2+ + h202-> Fe3+ +OH +OH-
OH is the hydroxyl radical - iron looses the e- and it goes to the OH- to make OH
18
Q
where is iron stored in the body?
A
ferritin -24 subunits allows Fe2+
19
Q
whats in the centre of the ferritin ?
A
feroxidase which oxidised the fe2 to fe3 and deposits it
20
Q
how do you test of anaemia ?
A
test for ferritin in serum as single subunits not the 24 seen normally , also should be in cells not outside
21
Q
how do cells get iron ?
A
have transferrin receptors on their surface which bind to diferric transferrin in the blood
22
Q
what does IRP stand for?
A
Iron response protein
23
Q
what binding site does it have?
A
for iron sulphur clusters
24
Q
what happens when iron is low with IRP?
A
they are left unbound, can then bind to iron responce elements ( stem and loop on RNA). can bind at 5’ or 3’ .
25
what happens if IRP bind to IRE at 3' ?
helps to stablises the message, stops degradation from nucleases therefore more transferrin receptor is made
26
what happens if IRP binds to IRE at 5'?
it blocks transcription of ferritin
27
how does the liver detect iron levels?
ratio between iron bound transferritin and non bound. liver then makes hepcidin when iron levels are high to block ferroporin being made which exports fe into the blood steam .
28
how is iron taken up in the digestive system ?
Dmt1 takes fe3+ into enterocytes then fe2 to ferroportin and into blood where its picked up by transferrin
29
what does hephasestin do?
converts fe2 to fe3 using its copper iron
30
what does Dmt1 do in endosomes?
pumps iron out of endosome which has the pathogen trapped to starve it or iron
31
what are the 3 theories for NRAMP1 ?
that its a super iron transporter to get rid of the final bits of iron in the pathogen
pumps iron into the endosome as a way of triggering the fenton reaction which would produced hydroxyl radicals to kill the pathogen
both Dmt1 and NRAMP1 pump iron out of the endosome, but you want the OH make by the bacteria not the endosome so h202 or superoxide diffuse into bacteria and tigger reaction .
32
how do bacteria scavenge iron and heme?
cause cells to lysis - blood
| bacteria has a HASA binding site for heme and sends out HASR to bind to heme and allow up take
33
what are siderophores?
small molecules which bacteria send out to get iron
34
what do siderophores cause?
competition between bacteria - only they can collect iron bound to their own siderophores
35
how does as host respond to siderophores?
produces siderocalins
36
what are the two main uses for copper in the body ?
respiration - cytochrome c oxidase, anitoxidants - super oxidase dismutase
37
whats the transporter for copper into cells?
Ctr1
38
how does Ctr1 work?
It has a negative entrance, selectivity filter with cystine residues which regulate copper flow, central cavity which is positive to push coper through to the exit which is negative
39
whats the copper transporter into compartments or out of cells ?
ATP7A/B
40
how many heavy metal binding domains do humans have ?
6
41
what do heavy metal binding domains do ?
regulate copper
42
what does ATP7A/B need to work?
ATP conformational change
43
What happens when copper is low?
ATP7A is present on the Golgi body ER and allowing proteins being made to obtain the copper
44
what happens when copper is high ?
ATP7A is moved to the cell surface and pumps the excess cu out of the cell into the serum
45
how seems ot regualte this cycling of atp7a?
motifs
46
what is an enterocyte?
cells which line the intestine
47
what are hepatocytes ?
liver cells
48
what form of ATP7 do liver cells have?
ATP7B
49
what happens when copper is high in ATP7B cells ?
ATP7B moves to the bile canaliculus and pumps cu into the bile
50
what causes menkes disease
ATP7A mutations , only has one heavy metal domian
51
what is a symptom of menkes ?
kinky hair
52
what causes wilsons disease?
ATP7B mutations
53
what happens in wilsons disease?
excess cu is not removed builds up in liver and causes liver damage
54
what roles do ATP7A/B have in cu transport in the brain ?
ATP7A - cu into spinal cord B - out
55
examples of some therapies used to treat wilsons and menkes ?
penicillimine - removes excess cu
| copper histidine - bypass ATP7A/B
56
what other metal can ATP7A/B and Ctr1 use?
platinum
57
what does cisplatin do?
prevents proliferation of rapidly / cells - cancer treatment
58
what mediates susceptibility/ resistance of cisplatin ?
Ctr1
59
two current theories for how cu is transported in plasma?
ceruloplasmin - mutlicopper oxide which has 4 tightly bound cu atoms but can weakly atrract others
Albumin - has a weak attraction for cu but is very common in plasma
60
How is too much cu toxic?
triggers the fenton reaction and mismetallation
61
whats the irving williams series ?
the prescribed binding order of metals - cu very high
62
if cu availability is kept very low, how does it get to where it needs to be ?
metallochaperones delivers cu to its locations
63
whats CCS?
copper chaperone for SOD
64
why are neurological disorders through to be linked to mis metallation ?
metals found in plaques
65
what is cobalt a cofactor of?
b12
66
what type of ring does b12 have?
corrin ring
67
how do you get variations of b12 ?
different groups attached to the lower ligand
68
how many states does cobalt have?
3- 1+,2+,3+
69
what are the two enzymes that need b12?
methylmalohyl Coa mutase and methionine synthase
70
what does methylmalonyl Coa mutase do
breaks down aa and produces a key molecule of TCA cycle
71
what happens if methmalonyl coa mutase mutates ?
leads ot methylmalonic acidemia and neurological issues
72
why is methionine synthase important?
produces methionine - starting amino acid of every protein
73
what happens when methionine synthase mutates ?
build up of homocysteine which can lead to blindness
| and megablastic anaemia - huge red blood cells
74
why does megablastic anaemia occur?
cause methionine is key for red blood cell maturation
75
which organisms made B12?
bacteria - only 30%
76
where at the 2 places that cobalt can be introduced into b12 in bacterial pathways ?
early - anaerobic
| late- aerobic
77
what enzyme is used to insert cobalt into b12 in the early pathway?
cbiK - chelatases
78
what is used to insert cobalt into b12 in the late pathway ?
cob W - chaperone
79
how do humans get B12?
through meat and dairy - cows have bac in their guts which produce b12
80
why do peas show symptoms of low cobalt ?
cause they have nitrogen fixing bac in their roots which need the cobalt to make b12
81
what does a decrease in b12 during pregnancy cause?
spina bifita
82
why do low b12 levels cause spinal defect ?
methionine synthase makes myelin for neurotransmitters
methylmalonyl Coa mutase reduced activity may cause an increase in methylmalonyl Coa which produces MMA (methylmalnic acid ) - destabilises myelin
83
why is a b12 deficiency increase with old age ?
less intrinsic factor is produced, intrinsic factor binds closely with b12 and thus is taken up via cubulin from the intestines
84
what happens if you have too much cobalt ?
neurotoxicity, pneumonia and lung cancer
85
what is MOCO?
molybdenum cofactor
86
what is MOCO needed for?
sulphite oxidase and xanthine oxidase
87
what does sulphite oxidase do?
detoxifies sulphite
88
what does xanthine oxidase do?
catabolism of purine
89
what happens if MOCO mutates in humans ?
toxic metabolites build up causes death
90
what is manganese needed for ?
mtSOD and glutamine syntheses
91
what does glutamine synthese do ?
recycles glutamate in neurotransmitters
92
what transports manganese ?
DMT1
93
what happens when you have too much manganese ?
similar symptoms to Parkinsons
94
what sequesters manganese in infections ?
calprotectin
95
why is lime disease so hard to treat ?
evolved not to use iron therefore bodies defences dont work to kill it
96
what percentage of all enzymes in the body need zinc?
9
97
what is zinc mainly used for?
structural roles such as zinc finger motifs
98
how did the prevalence of zinc change across evolution?
once the world became more aerobic , oxygen realesed zinc from zinc sulphur clusters by oxidation
99
what does zinc bind to in the finger motif ?
cysteine and histodine
100
why are zinc fingers useful?
they bring sections of the protein together creating a surface structure
101
where is zinc normally transported in ?
into cytoplasm from serum or into cells from vesicles
102
what transporter is associated with pumping zinc in?
ZIP
103
what transporters pump zinc out of cells?
ZNT
104
how is zinc levels within a cell regulated?
if zinc is too high zip transporter is endocytosed so no more zinc can be brought in, if too low then zip is made but cleaved to make it more efficient at zinc transport
105
what is the transporter for dietary zinc?
ZIP4
106
what causes acrodermatitus enteropathica ?
mutations in ZIP4 - treated with zinc supplements
107
how is zinc moved about the body?
via albumin - weak association but lots of them
108
how does albumin release the zinc?
needs fatty acids
109
how does zinc work in insulin produciton?
forms zinc insulin crystals within vessicle which then get released and the crystal dissolved
110
why might mutations in ZNT8 link to diabetes ?
ZNT is present at the beta cell surface in the pancreas and can be recognised as an antigen causing autoantibody production
111
what happens to zn levels in prostate cancer?
they decrease
112
what does aconitase have?
iron sulphur clusters
113
why does aconitase need to be turned off in the prostate?
to allow citrate production and lower ph
114
how is aconitase shut down?
via zinc
115
where is zinc stored?
metallotheronein (mt) which has alot os cysteine residues which binds 4 and 3 zn
116
what does MTF stand for?
metal transcription factor regulator
117
what does MTF1 have?
a weaker affinity for zinc than normal zinc finger motifs but it means that zinc only binds to it when zinc levels are higher than normal
118
when zinc is bound to MTF1 what happens?
MTF1 binds to the dna complex and interacts with MRE causing production of more metallothronein
119
what does MRE stand for?
Metal responce elements
120
how does cadmium also cause an increase in metallothronein ?
binds to MT causing zinc atoms ot be displaced leading them to bind to MTF1 increasing MT production
121
what roles does zinc have at the synapse?
shuts off glutamate receptor by binding to them
122
what is galvanising?
coating something in zinc
123
what holds zinc from bacteria?
calprotectin
124
what do bacteria produce to get host zinc ?
metallphore which competes with calprotectin
125
issue with host withholding all zinc ?
some bacteria grow better with a lower concentration of zinc
126
when does calprotectin actually start holding metals?
after it has been released from neutrophils and encounters high levels of calcium
127
what does PsaA do?
is a surface protein which bacteria use to get manganese
128
how does zinc interact with PsaA ?
binds to it , meaning the bacteria cant get manganese and are at risk of oxidative stress
