Biohemija metabolizma (Školska 2019/2020.)

UVODNO PREDAVANJE

dr Milan Nikolić, docent

Metabolizam obuhvata sve hemijske procese koji se dešavaju u ćeliji.

Mali podsetnik...

• Metabolizam služi da:

~ obezbedi energiju, razgradnjom energijom bogatih nutrijenata ili korišćenjem sunčeve energije

~ molekule nutrijenata prevede u prekursore za izgradnju biomakromolekula i ćelijskih komponenti

~ obrazuje ili razgradi biomolekule za specijalizovane funkcije ćelije

Energija je sposobnost obavljanja rada.

Živi sistemi crpe, pretvaraju, skladište i koriste energiju.

Energija je neophodna za biosinteze, transport, kretanje, itd.

Metabolizam = Hemijske transformacije

Metabolički tipovi živih sistema

(a) Prema izvoru ugljenika:

• Autotrofi – redukcija CO2 iz vazduha

• Heterotrofi – iz organskih jedinjenja

(b) Prema izvoru energije:

• Fototrofi – transformacija svetlosne energije

• Hemotrofi – oksidacija hemijskih jedinjenja

- hemoorganotrofi oksiduju organska jedinjenja

- hemolitotrofi oksiduju neorganska jedinjenja

Jedinjenja bogata energijom

• Energija dobijena procesima oksidoredukcije mora biti

sačuvana za različite potrebe.

• Energija se u živim sistemima pre svega se konzervira

u obliku fosforilisanih jedinjenja.

1-5 mM

Jedinjenja neophodna za konzerviranje energije

Mehanizmi konzervacije energije kod hemoorganotrofa

Fermentacija - redoks proces

se odvija u odsustvu spoljnog

akceptora elektrona

Respiracija (disanje) - postoji spoljni akceptor elektrona

- aerobna - akceptor elektrona je molekulski kiseonik

- anaerobna - akceptor elektrona je neko drugo, obično

neorgansko jedinjenje

• ATP nastaje u toku katabolizma

organskog supstrata

• Sinteza ATP-a na račun proton-motorne sile koja nastaje u toku

prenosa elektrona kroz respiratorni lanac (oksidativna fosforilacija)

• Respiratorna goriva: rezultat regulisane digestije i

apsorpcije nutrijenata ili (selektivne) mobilizacije

rezervnih molekula

(hemorganotrofi)

omnivrous vs. herbivors

Metabolički profil životinjskih ćelija

Različita sposobnost ćelija i organa

za korišćenje metaboličkih goriva

Mozak: 100145 g Glc dnevno

Kalorijska homeostaza

Metabolička povezanost organa

Principi regulacije metabolizma

• Prostorna odeljenost metaboličkih puteva

(različita metabolička aktivnost & izmena metabolita

između citosola i mitohondrija)

• Metabolička specijalizacija organa

• "Pace-maker" reakcije

(kontrolne tačke metaboličkih puteva)

• Ograničavajući metaboliti

(Indikatori energetkog stanja ćelije)

• Regulacija aktivnosti enzima

(alosterna regulacija; inhibicija proizvodom; regulacija

povratnom spregom; regulacija količine enzima)

• Hormonska regulacija

Glavni tipovi metaboličkih enzima

Struktura nekih od najvažnijih metabolita

Predznanja neophodna za

uspešno pohađanje kursa

• Osnovi organske hemije

• Osnovi fizičke hemije

• Osnovi enzimologije

• Osnovi biologije

A functional group is a group of

atoms within a molecule that has a

characteristic chemical behavior.

Acids and Bases The vast majority of biological transformations are catalyzed by acids or bases.

Brønsted–Lowry Acids and Bases

Lewis Acids and Bases

A Lewis acid is a substance that accepts an electron pair from a base,

and a Lewis base is a substance that donates an electron pair to an acid.

Lewis acids are involved in a great many biological reactions, often as

cofactors (e.g. metal cations) in enzyme-catalyzed processes.

An acid is a substance that donates a proton (hydrogen ion, H+), and a base

is a substance that accepts a proton.

Electrophiles and Nucleophiles

An electrophile is a

“electron-loving” substance.

Electrophiles are either positively

charged or neutral and have a

positively polarized, electron-poor

atom that can accept an electron

pair from a nucleophile/base.

A nucleophile, by contrast, is

“nucleus-loving” substance.

Nucleophiles are either negatively

charged or neutral and have a lone

pair of electrons they can donate to

an electrophile/acid.

Mechanisms: Electrophilic Addition Reactions

Biological examples are the biosynthetic routes leading to steroids and other terpenoids.

The mechanism of the acid-catalyzed electrophilic

addition of water to 2-methylpropene.

Mechanisms: Nucleophilic Substitution Reactions

Mechanism of the SN2 reaction of

(S)-2-bromobutane with hydroxide ion

to yield (R)-2-butanol.

Mechanism of the SN1 reaction of

2-bromo-2-methylpropane with water

to yield 2-methyl-2-propanol.

An SN2 reaction is involved in biological

methylation reactions (-CH3 group is

transferred from S-adenosylmethionine

to various nucleophiles).

Nucleophilic Carbonyl Addition Reactions

Some typical nucleophilic addition reactions of aldehydes and ketones. (a) With a

hydride ion as nucleophile, protonation of the alkoxide intermediate leads to an

alcohol. (b) With an amine as nucleophile, proton transfer and loss of water leads to

an imine. (c) With an alcohol as nucleophile, proton transfer leads to a hemiacetal,

and further reaction with a second equivalent of alcohol leads to an acetal.

In biological pathways, NADH or NADPH is the most frequently used hydride-ion donor.

Conjugate (1,4) Nucleophilic Additions

Nucleophilic Acyl Substitution Reactions

Mechanism of the nucleophilic acyl substitution

reaction of OH- with methyl acetate to give acetate. The carboxypeptidase-catalyzed hydrolysis

of the C-terminal amide bond in proteins.

Occur frequently in biochemistry!

Mechanisms: Carbonyl Condensation Reactions

Mechanism of the Claisen condensation, a reversible,

base-catalyzed condensation reaction between two

molecules of ester to yield a β-keto ester.

Mechanism of the aldol reaction, a reversible, base-catalyzed

condensation reaction between two molecules of aldehyde or

ketone to yield a β-hydroxy carbonyl compound.

Mechanisms: Elimination Reactions

Examples of all three mechanisms occur in different

biological pathways, but the E1cB mechanism is particularly

common, and the substrate is usually an alcohol (X=OH).

The mechanisms of two of the more commonly occurring biological redox processes:

the oxidation of an alcohol (a) and the reduction of a carbonyl compound (b).

Oxidations and Reductions

(a)

(b)

NADH transfers a hydride ion to the carbonyl group in a nucleophilic

addition reaction, and the alkoxide intermediate is protonated.

Base B: abstracts the acidic -OH proton, the electrons from the -OH bond move to

form a C=O bond, and the hydrogen attached to carbon is transferred to NAD+.

Kako (na)učiti metaboličke puteve

• Nije memorisanje informacija, već razumevanje strategija

koje organizam koristi da bi ostvario određeni cilj.

• Razmatrati svaki metabolički put kroz sve složenije nivoe:

Nivo 1 – Svrha i lokalizacija;

Nivo 2 – Glavne faze;

Nivo 3 – Sudbina ugljeničnog skeleta;

Nivo 4 – Energetski bilans;

Nivo 5 – Posebne karakteristike i specifičnosti;

Nivo 6 – Kontrolne tačke;

Nivo 7 – Detalji (intermedijeri, reakcije, enzimi).

+ veze sa drugim metaboličkim putevima!!!

1. O svrsi metaboličkog puta može da se zaključi

iz njegove opšte jednačine

2. Glavne (pod)faze metaboličkog puta

3. Sudbina ugljeničnog skeleta

4. Energetski "ulaz" i "izlaz"

5. Specifičnosti metaboličkog puta

6. Kontrola metaboličkog puta • (Svi) metabolički putevi nisu aktivni u isto vreme

• Promene u aktivnosti ključnih metaboličkih enzima

7. Detalji metaboličkog puta