# **Biochemistry**
midterm exam includes:
**lipids** and its **catabolism, synthesis**
**cholestrol** and **lipoprotein**
**degration, synthesis** of amino acid
**heme**

## wk1. lipids
* all biological lipids are amphipathic.
* common function of lipids: membrane, storage, messenger, protection, insultation (nerve transmition)
* membrane lipids: glycolipids (including sphingolipids), phospholipids
* storage lipids: fatty acid, triacylglycerol
* messenger: glycerophospholipids and sphingolipids acts locally while steroid act remotely as hormones
* protection: from water loss and physical shock
### 1.fatty acid
>catorized in 3 ways
with/without double bond: saturated/unsaturated
configuration of duble bond: trans/cis
>
>saturated FA has higher m.p.
and trans FA has higher m.p. if other condition ctrl.
>
>omega
>omega indicate where the first double bond appreas.
>the omega-3 fatty acid means that:
>from the end of the chain, the third carbon has double bond.

>carbon number
>e.g., C18:3 means that the chain includes 18 carbons and 3 double bonds.

>some important saturated acid
>|common name|numeric|
>| -:| -:|
>|butyric acid|4:0|
>|lauric acid|12:0|
>|myristic acid|14:0|
>|palmitic acid (PA)|16:0|
>|stearic acid (SA)|18:0|

>some **essential** FA
>|common name|numeric|omega|
>| -:| -:| -:|
>|oleic acid (OA)|18:1|omega-9|
>|**linoleic acid (LA)**|18:2|omega-6|
>|**alpha-linoleic acid (ALA)**|18:3|omega-3|
>|gamma-linoletic acid (GLA)|18:3|omega-6|
>|**arachidonic acid (AA)**|20:4|omega-6|
>|**eicosapentaenoic acid (EPA)**|20:5|omega-3|
>|docosapentaenoic acid (DPA)|22:5|omega-3|
>|**docosahexaeonic acid (DHA)**|22:6|omega-3|

>use of FA
>|catagory|function|
>|-|-|
>|omega-3|cardio-protective, anti-inflammatory, anti-carcinogenic|
>|omega-6|protaglandins, thromboxanes, leukotrienes syn.|

### 2.Triacylglycerols
>some facts:
>* compose of glycerol and 3 fatty acid
>* does not need a solvent
>* carbon is more reduced so that it's more efficient
>* oxidation of TG can produce water

### 3.Glycerophospholipids
>* compose of glycerol, 2 fatty acid and a phosphate

>different kinds of glycerophospholipids
>(記前三個就好)
>|name|x (取代基)|
>|-|-|
>|phosphatidic acid (PA)|hydrogen|
>|phosphatidylethanolamine (PE)|ethanolamine|
>|phosphatidylserine (PC)|choline|
>|phosphatidylserine (PS)|serine|
>|phosphatidylglycerol (PG)|glycerol|
>|phosphatidylinositol (PI)|myo-inositol-4,5-biphosphate|
>|cardiolipin|very big structure|

>ether lipids
>one of the acyl group has an ether linkage (-OR)
>(1) plasmalogens: about half of lipid in heart tissue
>
>
>
>(2) platelet-activating factor
>responsible for:
>* aggregation of platelet, release of serotonin,
>* regulation of inflammation/allergic response
>
>
>
>both the abovementioned are PC

### 4.sphingolipids
>* sphingolipids include the structure of sphingosine (a 18C alcohol)
>
>* the amine group links to a fatty acid
>* and hydroxyl group links to other groups (see below)
>* sphingolipids are sites of blood type recognition

>different kinds of sphingolipids
>|name|x (取代基)|
>|-|-|
>|ceramide|H|
>|sphingomyelin|phosphocholine(磷酸膽鹼)|
>|glucosylcerebroside|glucose|
>|lactosylceramide|di-, tri-, tetrasaccharide|
>|ganglioside GM2|complex oligosaccharide|

>ceramide
>* 50% of the intercellular lipids of a horned layer
>* lack of ceramide may cause dry skin

>spingomyelin
>* form the myelin sheath in neutal system

>cerebroside
>* beta-glycosidic linkage

>ganglioside
>* oligosaccharide that made of 3 or more sugars
>* and one of which is sialic acid
>* muscle / nerve membrane
>* nerve end, impluse transmition


### 5.waxes
> some facts
> * waxes are ester that combine long-chain fatty acid and long-chain alcohol, each 14-30 C, unbranced
> * common wax sources: animal fur or feather, plant leaves, stems, fruits

### 6.isoprene-based lipids
>* isoprene = 2-methyl-1,3-butadiene (2-甲基-1,3-二丁烯)
>* one or multiple terpene froms a variety of compounds, e.g., retinal is a diterpene

>coumadin (warfarin)
>* when being called coumadin, it is an oft-prescribed anticoagulant
>* called warfarin, it is a reodent poison
>* both of the mechanism is that coumadin is an antagonist of Vit. K:
>
>when clotting, amino acid Glu needs to add a carboxyl group at its gama site
>
>
>
>Vit K. faciliates GGCX, gamaglutamic carboxylase
>and by antagonising (oxdizing) Vit. K, glutamic acid will less likely attach to Ca+

>steroids
>* choelsterol is the precursor of many steriods

### 7.eicosanoids
>* act as **paracrine** hormones
>* some notable eicosanoids: prostaglandins, prostacyclins, thromboxanes, leukotrienes, epoxyeicosatrienoic acids.

### 8.glycerophospholipid metabolism
>* a phospholipid has two fatty acid chain attach to glycerol phosphate
>* the enzyme that cleave two fatty acid is called phospholipase A1, A2, respectively
>* the enzyme cleaves phosphate and the rest of phospholipid apart is called phospholipase C
>* the enzyme cleaves the attached group and phosphate apart is called phospholipase D
>

>* phospholipid that reacted with PLA1, A2 will lose one of its fatty acid chain and be called **lysophospholipid**
>* lysophospholipid looks like SDS, which is used as detergent, both of which has similar function
>e.g., lysolecithin is a product of PLA2, it can dissolve membrane of RBC, causing rupture

>some notable (glycero)phospholipids breakdown products:
>arachidonic acid(**AA**), lysophosphatidic acid(LPA), diacylglycerol (**DAG**), inositol phosphate (IP3)

## wk2. FA catabolism
### 1. sources of TG
#### 3 main sources
> * chylomicrons (food intake)
> * albumin (stored in adipocytes)
> * VLDL particles (carbohydrate synthesis)

#### process of ingestion
>* in the lumen of intestine, there's villi that absorb nutrients
>* the surface of villi lie enterocytes that have microvilli
>* emulsification: tearing apart fats(TG) with emulsifier (e.g., bile)
>* hydrolysis of TG by pancreatic and intestinal lipase
>* **pancreatic** lipase cleave fatty acid at **C1 & C3**
>* **intestinal** lipase, **C2**
>* villi absorb the fatty acids and monoacylglycerols and regenerate TG within enterocytes
>* the regenarated TG assemble with certain protein and be released to lacteal as chylomicrons

#### process of fatty acid transport by albumin
>* fat reservior occupy a great proportion of adipocyte
>* albumin: 40mg/mL in serum, provide 80% of osmotic pressure and act as buffer solute
>* free fatty acid soluability in blood is 0.1nM
>* bind to serum albumin, the soluability rise to 1mM (10,000 times)
>* the main receptor of FA is adipose and muscle tissue

### 2. (typical) beta oxidation
* the carbon next to carboxyl group in a fatty acid is called **alpha** carbon, the next, beta, and so forth
* oxidation at the bond between alpha and beta bond will produce acyl-CoA, 1 NADH and 1 FADH2
* 1 acyl-CoA will produce 3NADH, 1FADH2 and 1ATP
* natural antioxidants like catechins(綠茶兒茶素) can improve fatty acid oxidation and increase glycogen level in muscle cell

#### step 1: esterfication with CoA-SH
>* fatty acid bind to CoASH with needs 1 ATP and 1 Pyrophosphate as energy source
>* the first is the "investment" stage of beta oxidation
>**product: (fatty) acyl - CoA (ester)**

#### step 2: membrane transportation
>* fatty needs to be transport from cytosol to **Mt.**, where beta oxidation take place
>* carnitine can carry "R-C=O" part of acyl-CoA,and take the group to the martix of Mt.
>**midproduct: (fatty) acyl - carnitine (ester)**
>* acyl carnitine ester get into a mitochondion via carrier protein and regenerate acyl-CoA
>* after regeneration, carnitine get back to cytosol via the carrier protein
>

#### step 3: carbon backbone reaction sequence
3-1: **dehydrogenation**
>enzyme: acyl-CoA dehydorgenase = A**D**
>reaction: the two hydrogen on beta carbon removed, forming a double bond between alpha and beta carbon
>**product: trans-enoyl-CoA**, 1FADH2 = 1.5ATP
>(有一個丙烯基在alpha跟beta中間, enoyl)
>

3-2: **hydration**
>enzyme: enoyl-CoA hydrate = E**H**
>reaction: addition of water on beta carbon
>**product: 3-hydroxy acyl -CoA**
>(3號碳，就是beta，上有羥基)
>

3-3: **dehydrogenation**
>enzyme: 3-L-hydroxyacyl-CoA dehydrogenase = HA**D**
>reaction: remove the two hydrogen and make a C=O group at beta site
>**product: beta-ketoacyl-CoA**
>(羥基脫水變酮)
>

3-4: **thiolase** reaction (C-C cleavage)
>enzyme: beta-ketoacyl-CoA thiolase = K**T**
>reaction: cleave the bond between alpha and beta carbon
>After that, adds a CoA-SH on the "former" bata carbon (esterfication)
>**product: acyl-CoA and fatty acyl-CoA**
>(因為在beta處，新的碳氧雙鍵做好了，那舊的就可以放心離開，變成乙醯輔酶A)
>

>in step 3-1 AD (acyl-CoA dehydrogenase) has 4 varients
>very long chain, long chain, medium chain, short chain
>(VLCAD, LCAD, MCAD, SCAD)

#### calculation
a 16C fatty acid can generate:
>esterfication: -2ATP
>7 cleavage: 7FADH2 + 7NADH
>8 acyl-CoA: 8FADH2 + 24NADH + 8ATP
>
>15FADH2 = 22.5ATP, 31NADH = 77.5ATP
>total 22.5+77.5+8-2=106 (ATPs)
>
>byproduct: 123H20

### 3. odd carbon FA oxidation
* odd carbon FA generate acyl-CoA as even number carbon FA do, but in the end, it will produce **propionyl-CoA**
* the goal: make propionyl-CoA to succinyl-CoA
* the reaction involve Vit. B7 & B12
* **excessive** succinyl-CoA can be turned into **malate** via TCA cycle and be turned into **pyruvate** with the help of malic enzyme, which generates 1NADPH

### 4. unsaturated FA oxidation
* since the structure may not be "trans" as the step 3-2 (hydration) of beta oxidation required, it needs a **enoyl-CoA isomerase**
* the double bond needs to be between alpha and beta carbon, enoyl-CoA can also adjust them as step 3-2 required
* if two double bond, esp. one trans one cis, are beside each other, 2,4-dienoyl-CoA reductase reduce them and form a new double bond between the "former" two

### 5. alpha oxidation
* if the carbon number is excessive for beta oxdation, the oxidation of carboxylic group, which make the alpha carbon the new carboxylic group, is called alpha oxidation
* after trimming by alpha oxidation, beta oxidation can generate propionyl-CoA and acyl-CoA
* the enzyme involved is called phytanic acid oxidase or alpha-hydroxylase
* lack of the enzyme will cause **Refsum's disease**

### 6. omega oxidation
* omega means the farest carbon from carboxyl group
* when beta oxidation within mitochondria cannot function(lack of carnitine or mutation), omega oxidation is a minor but important substitution
* omega oxidation occur in **ER**
* the opposite side of carboxyl group in FA is oxidize and become another carboxyl group
* after the second carboxyl group formed, beta oxidation starts, producing **succinate and adipate (dicarboxylic acid, DCA)**
* the reaction requires **cytochrome P450**


### 7. peroxisomal beta oxidation
* uusally use long chain and branched FA to make heat in peroxisomes
* in peroxisomes, FADH2 is not taken to ETC that generate ATP, rather, FADH2 is used to make H2O2
* catalase decompose H2O2 into H2O and O2, dissipating heat
* for plants, normal FA catalysis occur in peroxisome rather than mitochondria

### 8. ketone bodies
  

* acetone, acetoacetate and 3-hydroxybutyric acid are called ketone bodies
* the former 2 possess a carbonyl group, the latter 2 are not ketone but carboxylic acid
* ketone bodies are water suluable so that it can be seen as a transporatble form of FA (3mg/mL in human blood)

#### synthesis of ketone body
>* the reaction occur in **mitochondrial matrix of liver cell**
>* amino acid, FA, glycolysis can all generate acyl-CoA
>* 2 acyl-CoA binds together, making acetoacetyl-CoA
>* add another acyl-CoA on the third carbon, making 3-hydroxy-3-methylglutaryl-CoA (HMG-CoA)
>* HMG-CoA decompose, generating 1 acyl-CoA and 1 **acetylacetate**
>
>* by oxidizing the carboxyl group, acetylacetate turn into acetone
>* by hydrogenating the carbonyl group, acetylaccetate turn into beta-hydroxylbutyrates
>
>|reaction|input|output|enzyme|
>|:-:|:-:|:-:|:-:|
>|1|2acyl-CoA|acetylacetyl-CoA|thiolase|
>|2|acetylaccetyl-CoA, acyl-CoA|HMG-CoA|HMG-CoA synthase|
>|3|HMG-CoA|acetoacetate, acyl-CoA|HMG-CoA lyase|

#### use of ketone bodies
>in muscle or other peripheral tissues, ketone bodies reconverse to acyl-CoA and join the TCA cycle and generate ATP

#### diseases
>ketosis induced acidosis:
the pH value is too low when ketone bodies level rise,
which may lead to coma or even death

>type I diabetes:
starving cells turn to glucogenesis or fat/protein catabolism
excessive glucogenesis **depletes OAA**, which is essential for TCA cycle
after glucolysis, excessive acyl-CoA had no choice but turn into ketone bodies
as a result, acetone can be detected on breath

## wk3. lipid biosynthesis
### 1. synthesis versus catabolism
||synthesis|catabolism|
|:-:|:-:|:-:|
|when|after carbohydrate-rich meal|in starvation|
|hormonal state|high insulin/glucagon ratio|high glucagon/insulin ratio|
|activator|citrate||
|inhibitor|palmityl-CoA (or other fatty acyl-CoA) --> ACC|malonyl-CoA --> carnitine acyltransferase|
|where (organ)|liver|liver and muscle|
|where (cellular)|cytosol|mitochondria|
|transmembrane carrier|citrate (M to C)|camitine (C to M)|
|required coenzyme|NADPH|NAD+, FAD|
|essential midproduct|Acyl carrier protein (ACP)|CoA|
|product|palmitate, CO2|acyl-CoA|
|isomer|D-isomer|L-isomer|

### 2. material for synthesis
#### source of material
>(citrate and pyruvate can pass through the inner membrane of mitochondria)
>* excessive acyl-CoA get into TCA cycle, become citrate and **get to cytosol**
>* citrate can regenerate **acyl-CoA**
(citrate-malate-pyruvate shuttle)
>* citrate ---ATP citrate lyase---> OAA
>* OAA ---malate dehydrogenase---> malate (cost: 1NADH)
>* malate ---malic enzyme---> pyruvate + CO2 (yeild: **1NADPH**)

#### malonyl-CoA
>is acyl-CoA acutually the material for FA syn.?
>yes, and no.
>
>in first place, acyl-CoA should turn into **malonyl-CoA** which actually participate in the reaction
>
>acyl-CoA + CO2 ---> malonyl CoA (cost: 1ATP)
>

#### acyl-CoA carboxylase
>this **irreversible** reaction (**comitted** step) requires acyl-CoA carboxylase (ACC), which is the **rate-controlling** enzyme of FA syn.
>
>in bacteria:
>* ACC is composed of 3 different proteins
>(1) biotin carrier (2) biotin carboxylase (3) transcarboxylase
>
>in eukaryotes:
>* ACC is composed of 2 identical peptides, which is **inactive** in **dimer (or protomer)** form but **active** in **polymer** form
>* ACC is activated by the material, citrate (by phosphorylation at Pi-S1200); supress by the product, palmitoyl-CoA (allosteric feedback inhibition or phospholation on protein)
>

### 3.steps of biosynsthesis
#### step 1: condensation
>|material|enzyme|product|
>|-|-|-|
>|malonyl-CoA|--MAT-->|malonyl-ACP|
>|acyl-CoA|--MAT-->|acyl-ACP|
>|malonyl-ACP + acyl-ACP|--KS-->|acetoacetyl-ACP + CO2 + ACP-SH|
>
>in the reaction, acyl-ACP cleave ACP
>malonyl-ACP oxidize its carboxyl group, adding to acyl-ACP (and make CO2)
>
>MAT: **m**alonyl/**a**cyl-CoA-ACP **t**ransacylase
>KS: beta-**k**etoacyl-ACP-**s**ynthase

#### step 2: reduction
>|material|enzyme|product|
>|-|-|-|
>|acetoacetyl-ACP|--KR-->|beta-hydrobutyryl-ACP|
>
>cost: 1NADPH
>in the reaction, the carbonyl group (C=O) is reduced into hydroxyl group (C-OH)
>
>KR:　beta-**k**etoacyl-ACP-**r**eductase
#### step 3: dehydration
>|material|enzyme|product|
>|-|-|-|
>|beta-hydrobutyryl-ACP|--DH-->|alpha,beta-transbutenoyl-ACP|
>
>in the reaction, a water is removed and a double bond is formed
>
>DH: ~ **d**e**h**ydrase
#### step 4: reduction
>|material|enzyme|product|
>|-|-|-|
>|alpha,beta-transbutenoyl-ACP|--ER-->|butyryl-ACP|
>
>cost: 1NADPH
>in the reaction, 2 hydrogen is added, reducing the double bond
>
>ER: **e**noyl-ACP-**r**eductase
>

#### calculation
>a 16C palmitic acid requires:
>acyl-CoA to malonyl-CoA: -1ATP (x7)
>adding a malonyl-CoA to the chain: -2NADPH (x7)
>
>total: 7ATP + 14NADPH
>byproduct: 7CO2

### 4.FA enlongation and desaturation
#### elongation
> the common product of FA syn. is **palmitate (16:0)**, which is synthesized in **cytosol**
> larger FA is synthesized in **ER**
> the enlongation steps are similar to normal biosynthesis, but the energy source of **step 2** is **NADH**

#### unsaturation
>e.g., from steric acid (18:0) to oleic acid (18:1, omega-9)
>to form a double bond (reduction), it requires electron from co-enzymes
>electron passed on from:
>**NADH** ---> FADH2 ---> cytochrome b5(reduced) ---> **desaturase (Fe2+)** ---> stearoyl-CoA (omega-9 carbon)

>mammals cannot certain kinds of FA since we don't have certain elongation/unsaturation enzymes
>those which we cannot synthesized are called "essential FA"

### 5. regulation
#### [ACC regulation](https://hackmd.io/_FbNZi9-S3GETj3oe-aCHw?view#acyl-CoA-carboxylase)
>acyl-CoA carboxylase is the comitted step in FA syn.
>citrate activates ACC and palnityl-CoA inhibit it
#### carnitine acyltransferase
>both palmityl-CoA and malonyl-CoA can block it, thus stopping beta-oxidation
>(when cell is nourished, FA is synthesized and thus beta-oxidation is not favoured)
#### hormone regulation
>glucagon can activate **protein kinase** via **cAMP**
>insulin can activate phosphodiesterase, tuning cAMP to AMP, thus stopping the following reaction
>
>PKA activate **TG lipase** and **inhibit ACC**
>i.e., PKA endorse FA degration and inhibit FA synthesis
>(protein kinase (active) is shortened as PKA)

### 6. complex lipids synthesis
#### syn. of TG
>the reaction in **hepatocyte**:
>
>glycerol
>--- glycerokinase---> glycerol-3-phosphate (G3P,磷酸甘油醛)
>--- G3P acyltransferase---> 1-acyl-G3P (MAG,磷酸化單酸甘油酯)
>--- ~ acyltransferase---> phosphatidic acid (PA, 磷脂酸，磷酸化雙酸甘油酯)
>--- ~ phosphatase---> 1,2-diacylglycerol (DAG,雙酸甘油酯)
>--- ~ acyltransferase---> triacylglycerol (TG,三酸甘油酯)

>other pathway (in **adopocyte**):
>glycolysis ---> DHA-phosphate
>--- 1NADH---> **G3P**
>or
>--- acyltransferase---> 1-acyl-DHA-phosphate
>--- 1NADPH---> **1-acyl-G3P**

>some facts
>* 75% of FA that released by lipolysis is reesterfied to form TG
>* hepatocytes can synthesize TG without glucose (by using glycerol),
>but adopocytes cannot
#### syn. of [phospholipid](https://hackmd.io/_FbNZi9-S3GETj3oe-aCHw?view#3Glycerophospholipids)
>review of phospholipids
>* phospholipid can be categorized by the func. group attach to phophate, the simplest phospholipid is phosphatidic acid
>* PA --- ~ phosphatase---> DAG
>* DAG can be turned into PC, PE, and TG (see above)

>syn. of other phospholipids
>* the nucleotide **CDP** can carry the func. group that add to DAG, **giving out a phosphate and the func. group**
>* the enzyme required to make PC or PE names after the product
>e.g., DAG + CDP-choline ---> phosphotidylcholine
>the enzyme is called 1,2-diacylglycerol phosphocholine transferase
>(1,2-diacylglycerol = phosphotidyl)
>* cardiolipin:　(FA)2-glycerol-Pi-glycerol-(FA)2
>* cardolipin is the major lipid of Mt. and it has an important role in ETC

>syn. of spingolipids
>* palmytoyl-CoA + serine ---> ceramide
(the reaction consume 1NADPH)
>* after synthesizing ceramide, addition on head group and addition of suagr make the variety of spingolipids
>* the sugar attach to ceramide is carried by UDP

>syn. of eicosamoid
>* eicosnoid is the most potent signalling compound in human body
>* thus, it produced in very small amount and has very short half-life
>* PG, TX, LT, are synthesized from **unsaturated fatty acids**, have 3-5 **double bonds**, and are most common **arachidonic acids**
>* PG and TX use COX (cyclooxygenase), while LT use lipoxygenase
>* anti-inflammatory drugs: block PG production
corticosteroids ---> PLA2; NSAID ---> COX 1&2

>NSAID
>|act on|irreversible|reversible|
>|-|-|-|
>|COX 1&2|aspirin (serine acylation)|acetaminophen, ibuprofen|
>|COX 2 only|celebrex||
>
>COX1 func.
>* protect stomach lining
>* decrease fever
>* clot
>
>COX2 func.
>* trigger pain and inflammation
>**thus, drugs that only act on COX2 have less side effects**
## wk4.cholesterol synthesis
### 1.cholesterol 101
>structure of cholesterol
>
> 

>some facts about cholesterol
>* member of membrane
>* precursor of bile salt, steriod hormone, Vit.D
>* mainly produced in ER of hepatocytes
>* the only material is acyl-CoA

>source of cholesterol
>* de novo syn.
>* diet
>* syn. in extrahepatic tissues

>outlet of cholesterol
>* stored in lipid droplet (as chol. ester)
>* secretion of HDL & VLDL to blood (as chol. ester)
>* release to bile
>* conversion to bile salt/acids
### 2.synthesis of cholesterol
#### DPP (5C)
> 2acyl-CoA
> ---thiolase---> acetoacetyl-CoA
> ---HMG-CoA synthase---> HMG-CoA
> --- ~ reductase, 2NADPH---> mevalonic acid
> ---3ATP---> IPP + **CO2**
> --- ~ transferase---> DPP
#### squalene (30C)
> IPP + DPP = GPP
> GPP + DPP = FPP
> FPP + FPP = squalene
> (using squalene synthase, 1NADPH)
#### cholesterol (27C)
> squalene
> --- ~ monoxygenase, 1NADPH--->squalene-2,3-epoxide (氧雜環)
> --->--->---> cholesterol


### 3.regulation of chol. syn.
#### HMG-CoA reductase
>* phosphorylation:
the patheway use cAMP as the messenger from hormone to protein kinase
>(this kinase is called adenosine monophosphate-activated protein, or **AMPK**)
>* halflife:
the higher chol. level, the lower halflife of the reductase
>* genetic expression:
the higher chol. level, the lower mRNA level
>
>|promote|inhibit|-|
>|-|-|-|
>|insulin|glucagon, AMPK (phosphorylation), oxysterol >(proteolysis)|-|
#### sterol regulatory elements-binding protein
>* when sterol level is high, protein insig binds to sec on ER membrane
>* when sterol level **goes down**, sec binds to SCAP-SREBP and escort the complex to Golgi apparatus
>* in Golgi apparatus, regualrtory domain of SREBP is released
>* the regulatory domain get into nucleus and promote lipid syn. enzymes
>* the name of SREBP indicates that it contain the regulatory domain
>* SCAP, or SREBP cleavage activating protein, promote the release of regulatory domain in Golgi apparatus
#### acyl-CoA:cholesterol acyl transferase
>* when chol. level goes up, it promote ACAT
>* ACAT turns chol. into chol. esters
#### drug control
>* statins: inhibit (competitively) HMG-CoA to slow down de novo syn.

### 4.bile salts 101
>* act as emusifier to dietary lipids
>* synthesized in the liver and stored in gallbladder
>* enterohepatic circulation: bile salts in GI tract reabsorbed to the liver
>* excretion in feces as a way to do with **excessive chol.**
>* only bile salts, not acid, are found in the bile
### 5.syn. of bile salts
>* chol./bile acid conjugated with Glycine or Taurine by amide linkage
>* bile salts are more likely to inoized beacuse of the COO- and SO3-
>* bile salts would deconjugate and dehydr oxylate in intestine, losing added amino acid and OH
>* bacteria can help to convert primary to secondary bile acids or regenerating bile acids

primary and secondary bile acids
### 6.cholelithiasis
>* the liver secrete bile salts with phospholipid to the gallbladder
>* if chol. is excessive, it may percipitate in the gallbladder and cause cholelithiasis
### 7.steroid hormone
>glands that secrete steroid hormone
>|gland|hormone|
>|-|-|
>|adrenal cortex|aldosterone (mineralcorticoids), cortisol (glucocorticoids), androgens [from outer to inner]|
>|testis|testosterone|
>|ovaries|estrogens, progesterone|

>* steroid hormone are derived from chol. and differ only in the ring structure and side chain attached to it
>* these gland gain chol. from LDL by endocytosis
>* adreno cortical cells can synthesize chol. itself
>* the rds in the biosynthesis of steroid hormone involve **cytochrome P450 side chain cleavage (P450 scc) enzyme**
>* testosterone can promote anabolism, so it is prohibited to atheletes
### 8.Vit. D
>* Vit. D3 (cholecalciferol) synthesized in skin when expose to sunlight
>* cholecalciferol convert to calcidiol in liver
>* calcidiol convert to calcitriol in kidney (active form)


## wk4. lipid transport
### 1.lipoprotein 101
>* lipoprotein consist of lipids and proteins (as follow)
>
>* the structure of lipoprotein are as follow, with hydrophilic side of proteins, phospholipids and chol. towards out
>

### 2.diffferent type of lipoprotein
>* particle size: chylomicron > VLDL > VDL > HDL
>* TG (%): chylomicron > VLDL > VDL > HDL
>* density: chylomicron < VLDL < VDL < HDL
>* protein: chylomicron < VLDL < VDL < HDL

>|lipoprotein|lipid of the greatest %|apolipoprotein|syn. site|
>|-|-|-|-|
>|chylomicron (CM)|TG|B-48, E, C-II, A|intestinal mucosal|
>|very low density lipoproteins (LVDL)|TG|B-100, E, C-II|liver|
>|low density lipoproteins (LDL)|chol.|B-100, ...|VLDL circulation|
>|high density lipoproteins (HDL)|chol.|E, C, A (mainly A)|peripheral cells|

>fate of chylomicron
>* when CM enter vessels, HDL pass its **apo-C-II and apo-E** to CM
>* tissues such as adipocyte absorb and degrade some of the TG in CM and thus, apo-C-II goes back to HDL
>* since TG is absorbed, proportion of chol. and chol. ester rise in CM
>* the CE-rich CM remnant bind through apo-E on hepatocyte
>* summary, peripheral tissues get TG, liver cells get chol.

>fate of VLDL
>* the fate of VLDL is very much that of CM
>* after TG absorbing, apo-B-100 binds to extrahepatic tissue and be endocytosed

>fate of LDL
>* LDL derived from VLDL, it can send chol. from liver to others
>* LDL is chol.-rich and can be absorbed by cells via receptor-mediated endocytosis
>* after endocytosis, receptor is sent back to cytomembrane
>* diferent cells have different ways of use of chol., e.g., cell membrane, steroid hormone (hepatocytes)
>
>* regulation: when the cell has enough or excessive amount of chol., the **oxysterol will inhibit endocytosis**;
>meanwhile, chol. promotes ACAT and turning it into chol. ester, and chol. inhibit HMG-reductase to decrease chol. level
>* disease:
familial hypercholesterolemia = defect in LDL receptor (cell can't absorb LDL so that it remain in vessels)
atherosclerosis = macrophage take in LDL, making foam cell, which will hurt endothelium cells...

>fate of HDL
>* lecithin-chol. acyl transferase (LCAT) can esterify chol.
>* the enzyme apo-A1 is associated with the activity of LCAT
>* cholesteryl ester transfer protein (CETP) can exchage CE for TG with VLDL, so that HDL and VLDL gradually become LDL
>* summary, HDL collects chol. from peripheral tissues, exchanges chol. for TG with VLDL, and VLDL carries chol. back to the liver
>* the func. of HDL:
uptake of chol., reservoir of apo., esterification of chol.

## wk.5 amino acid metabolism
### 1. nitrogen metabolism
#### dietary proteins lyase
>|organ|precursor|activator|enzyme|func.|
>|-|-|-|-|-|
>|stomach|pepsinogen|HCl|pepsin|15% protein ---> peptide|
>|pancreas|trypsinogen|enterokinase|trypsin|polypeptide ---> di, tripeptide|
>|pancreas|chymotrysinogen proelastase|trypsin|chymotrypsin elastase|~ ---> di, tripeptide, amino acid|
>|pancreas|procarboxypeptidase|trypsin|carboxypeptidase A&B|~ ---> di, tripeptide, amino acid|
>|intestine|-|-|aminopeptidase|~ ---> di, tripeptide, amino acid|

### 2.protein degradation
#### ATP-independent/dependent protein degradation
>lysosome: independent
>26S proteasome: dependent (attach to ubiquitin
>the 26S proteasome is the "garbage disposer" in a cell

#### three enzymes related to proteasome
>the 3 enymes are:
>* E1: ubiquitin-activating enzyme
>* E2: ubiquitin-conjugating enzyme
>* E3: ubiquitin ligase

>the steps:
>* E1 bind to a ubiquitin
>* E1 pass ubiquitin to E2
>* E3 bind to E2-ubiquitin
>* E3-E2-ubiquitin bind to target protein
>* one target protein can bind to many ubiquitin (polyubiquitination)
>* after the target get into proteasome, ubiquitin is recycled

>thus the ubiquitin is called the "death tag" (2004 Nobel

### 3. amino acid degradation
#### some facts
>* AA can be seprated into 2 parts: carbon skeleton and amino group
>* seperate the two parts requires **anino transferase** (12 enzyme for 20 AA)
>* the carbon skeleton tunr into pyruvate and subsequently become material for FA or carbohydrates
>* in low insulin/glucagon ratio,
>* AA can be turned into bases of nucleotides
>* AA can also be turned into ammonia via **urea cycle**

#### example (memorize)
>* the carbon chain resdue can be turned into pyruvate, acyl-CoA, acetoactate or acyl-CoA and members of TCA cycle
>* 3C alanine ---> pyruvate
>* 4C aspartate ---> oxaloacetate (OAA)
>* 5C glutamate ---> alpha-ketoglutarate
>* all the products can be generized as "alpha-keto acid"

#### glucogenic and ketogenic
>* those which generate TCA cycle participants or pyruvate are glucogenic; those which generate ketone bodies are ketogenic
>
>|glutogenic|both|ketogenic|
>|-|-|-|
>|Ala, Arg, Asp, Asn, Cys, Met, Glu, Gln, Gly, His, Pro, Ser, Thr, Val|Tyr, Iso, Phe, Try|Leu, Lys|
>
>|family|members|product|
>|-|-|-|
>|C3|Ala, Ser, Cys, Gly, Thr, Trp|pyruvate|
>|C4|Asp, Asn|OAA|
>|C4|Asp, Phe, Tyr|fumarate|alpha-ketoglutarate|
>|~|Ile, Met, Val|succinyl-CoA|
>|~|Ile, Leu, Thr|acyl-CoA|
>|~|Leu, Lys, Phe, Tyr, Trp|acetoacetate|

#### branched and non-branched
>* nonbranched chain AA (NBCAA) undergo transaminonation in **liver**
>* branched chain AA (e.g, Leu, Ile, Val), muscle
>* muscle must remove the amino group of BCAA before releasing them, but not NBCAA
>
>* the reaction is reversable, menaing **AA synthesis also use this pathway**
>* **pyridoxal-5'-phosphate (PLP)** is an coenzyme that present in all aminotransferase
>* PLP is the active form of **Vit. B6**

#### futher about BCAA catabolism
>* **Leu, Ile, Val** are branched chain amino acids
>* in muscular cells, the amino group of BCAA is transferred to glutamate, making **Ala** and goes to the **liver**, or making **glutamine** and goes to **kidney**
>
>

>* after transferring the amino group, alpha-keto acid is can be turned into acyl-CoA
>* such reaction requires **branched chain ketoacid dehydrogenase (BCKD)**, which is the **rds** of BCAA catabolism
>* defectibe BCKD leads to **maple syrup urine disease (MSUD)**

#### maple syrup urine disease (MSUD)
>* excessive BCAA in bloodstream, leading to maple syrup-esque urine
>* excessive ketoacids in blood, causing **ketoacidosis**
>* encephalopathy and coma
>* the treatment is mostly dietary control (not consuming BCAA)

### 4. urea cycle
>in nitochondria
#### step 1 carbamoyl phosphate syn.
>2 HCO3- ---CPS I, **2ATP**---> carbamoyl phosphate
>

#### step 2 citrulline syn.
>carbamoyl phosphate + ornithine ---OTC---> citrulline

>in cytosol
#### step 3 argininosuccinate syn.
citrulline + aspartate ---ASS---> arigininosuccinate

#### step 4 cleavage of argininosuccinate
argininosuccinate ---> argnine + fumarate

#### step 5 regeneration of ornithine
arginine + H2O ---> **urea + ornithine**

#### note
>* the two nitrogen in urea is from **carbamoyl and aspartate**
>* the carbon of urea is from **carbamoyl**
>* urea is then sent to live to be turned into urine

### 5. regulation of urea cycle
#### positive
>* N-acylglutamate: allosteric, CPS I
>* glucagon/cortisol: gene, transcription

#### negative
>* acidosis: allosteric, pH of blood (the lower the slower)
>* decreased beta-oxidation: less ATP, less urea cycle

### 6. inherited disease link to AA metabolism
>|disease|correlated AA|description|symptoms|
>|-|-|-|-|
>|albinism|Tyr|melanin syn. from Tyr|白化症:無法由Tyr合成黑色素|
>|alkaptonuria (AKU)|Tyr|Tyr degradation|黑尿症:放在空氣中一陣子就變黑、關節炎、發育遲緩|
>|homocystinuria (Marfan syndrome)|Met|Met degradation (turn into hemocystine rather than Cys)|骨骼發育問題、智障|
>|MSUD|BCAAs|BACC dehydrogenation|嘔吐、智障、早夭|
>|phenylketonuria (PKU)|Phe ---> Tyr|Phe dehydrogenation|嘔吐、智障，不可以吃代糖|

## wk7. Heme
### 1. homoglobin 101
>* the core of alpha or beta chain, heme group is made of porphyrin group and an iron ion
>* porphyrin can link to many other metal ion to function differently
>* a porphyrin has 4 acetate groups and 4 propionyl groups, with which we can catagorize heme
>
>* hemes are synthissed in **bone marrow (85%) and liver (15%)
>* material of heme includes **succinyl-CoA and glycine

### 2.biosynthesis of porphyrin
> 8 steps, the fist step in mitochondria, then 4 steps in cytosol, the rest in mitochondria

#### step 1: ALA
>1succinyl-CoA + 1Gly ---ALA synthase--->
>1omega-aminolevulinic acid (ALA) + CO2
>
>the reaction release a CO2

#### step 2: BPG
>2ALA ---ALA dehydratase---> 1PBG
>PBG is the intermediate of one of the 4 pyrrole ring of heme
>
>the reaction is sensitive to heavy metal poisoning

#### step 3: HMB
>4PBG ---HMB synthase---> 1HMB
>
>the reaction forms a chain of 4 PBG without closing the ring

#### step 4: uroporphyrunogen
>1HMG ---> uroporphyrunogen
>
>there are many kinds of porphyrin, type I has symmatric P, A group arrangement while type III don't

#### step 5: coproporphyrinogen
>uroporphyinogen --- ~ decarboxylase--- > coproporphyrinogen
>
>losing 1 CO2 at each side while closing the ring
>acetate ---> methyl

#### step 6: photoporphyrinogen
>coproporphyrinogen --- ~ oxidase---> photoporphyrinogen
>
> propionate ---> vinyl

#### step 7: activation of photoporphyrinogen
＞photoporphyrinogen --->　photoporphyriｎ

#### step 8: addition of iron
>Fe 3+ cna link to an anion via ionic bond
>if the anion is Cl-, the whole complex is called "hemin"
>if OH-, hemeatin
###### tags: `midterm`, `biochemistry`