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Sterol Side-Chain Methylation in Unc...

Brown, Malory Onessa.

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Sterol Side-Chain Methylation in Uncultured Bacteria.

Record Type:	Electronic resources : Monograph/item
Title/Author:	Sterol Side-Chain Methylation in Uncultured Bacteria./
Author:	Brown, Malory Onessa.
Published:	Ann Arbor : ProQuest Dissertations & Theses, : 2023,
Description:	155 p.
Notes:	Source: Dissertations Abstracts International, Volume: 85-06, Section: B.
Contained By:	Dissertations Abstracts International85-06B.
Subject:	DNA methylation. -
Online resource:	https://pqdd.sinica.edu.tw/twdaoapp/servlet/advanced?query=30726851
ISBN:	9798381021264

Sterol Side-Chain Methylation in Uncultured Bacteria.
Brown, Malory Onessa.

Sterol Side-Chain Methylation in Uncultured Bacteria. - Ann Arbor : ProQuest Dissertations & Theses, 2023 - 155 p.

Source: Dissertations Abstracts International, Volume: 85-06, Section: B.

Thesis (Ph.D.)--Stanford University, 2023.

This item must not be sold to any third party vendors.

Sterols are polycyclic triterpenoid lipids required by eukaryotes for many critical cellular functions. In addition, sterols are quite recalcitrant and are preserved as sterane molecular fossils, or biomarkers, in sedimentary rocks up to 1.6 billion years old. Given the persistence of these molecules in ancient rocks and their wide distribution amongst extant eukaryotes, geologists often interpret steranes broadly as biomarkers of past eukaryotic life, although diverse bacteria are also known to produce sterol lipids. Sterols with certain modifications to the side-chain, such as methylations at the C-24 position, can act as more specific biomarkers given their restriction to certain eukaryotic lineages and absence in cultured bacteria. One such side-chain methylated sterane biomarker, 24- isopropylcholestane (24-ipc), has historically been attributed to sea sponges of the Demospongiae class. 24-ipc first appears in the Cryogenian and may therefore represent the first evidence of animals on Earth. However, enzymes that produce sterols with the 24- isopropyl side-chain have not been identified in any extant organism. In this dissertation, I investigate the biochemical requirements for sterol side-chain propylation and explore the potentional for sterol side-chain methylation in yet-uncultured bacteria more broadly through a combination of laboratory experiments and bioinformatic analyses. In Chapter 1, I find that several bacterial sterol methyltransferases (SMTs) identified in metagenomes methylate the sterol side-chain in vitro and identify three bacterial SMTs that produce sterols with the 24-isopropyl side-chain of the 24-ipc biomarker. Several functional metagenomic SMTs occur in sterol biosynthesis gene clusters suggesting yet-uncultured bacteria have the genomic capacity to produce side-chain alkylated sterols de novo. In Chapter 2, I identify a necessary but not sufficient glycine residue conserved among propylating bacterial SMTs that occurs in the active site of SMT model structures. The presence of this glycine residue can therefore act as indicator of an SMT's ability to produce 24-isopropyl sterols. In Chapter 3,I find that bacterial SMTs are widely distributed in the environment but are particularly enriched in sponge metagenomes. Bacterial SMTs are actively transcribed in wastewater, soil, creeks, hot springs, and estuaries. Together, the results presented in this dissertation suggest bacteria may be an overlooked source of side-chain methylated sterols in the rock record, provide a framework for predicting SMT function directly from sequencing data, and highlight environments that can be targeted for future cultivation of bacteria that produce side-chain methylated sterols. Overall, this work demonstrates how techniques in molecular biology, biochemistry, and bioinformatics can be leveraged to improve the interpretation of molecular fossils.

ISBN: 9798381021264Subjects--Topical Terms:

3560639
DNA methylation.

Sterol Side-Chain Methylation in Uncultured Bacteria.
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300 $a 155 p.
500 $a Source: Dissertations Abstracts International, Volume: 85-06, Section: B.
500 $a Advisor: Francis, Christopher;Sperling, Erik;Welander, Paula.
502 $a Thesis (Ph.D.)--Stanford University, 2023.
506 $a This item must not be sold to any third party vendors.
520 $a Sterols are polycyclic triterpenoid lipids required by eukaryotes for many critical cellular functions. In addition, sterols are quite recalcitrant and are preserved as sterane molecular fossils, or biomarkers, in sedimentary rocks up to 1.6 billion years old. Given the persistence of these molecules in ancient rocks and their wide distribution amongst extant eukaryotes, geologists often interpret steranes broadly as biomarkers of past eukaryotic life, although diverse bacteria are also known to produce sterol lipids. Sterols with certain modifications to the side-chain, such as methylations at the C-24 position, can act as more specific biomarkers given their restriction to certain eukaryotic lineages and absence in cultured bacteria. One such side-chain methylated sterane biomarker, 24- isopropylcholestane (24-ipc), has historically been attributed to sea sponges of the Demospongiae class. 24-ipc first appears in the Cryogenian and may therefore represent the first evidence of animals on Earth. However, enzymes that produce sterols with the 24- isopropyl side-chain have not been identified in any extant organism. In this dissertation, I investigate the biochemical requirements for sterol side-chain propylation and explore the potentional for sterol side-chain methylation in yet-uncultured bacteria more broadly through a combination of laboratory experiments and bioinformatic analyses. In Chapter 1, I find that several bacterial sterol methyltransferases (SMTs) identified in metagenomes methylate the sterol side-chain in vitro and identify three bacterial SMTs that produce sterols with the 24-isopropyl side-chain of the 24-ipc biomarker. Several functional metagenomic SMTs occur in sterol biosynthesis gene clusters suggesting yet-uncultured bacteria have the genomic capacity to produce side-chain alkylated sterols de novo. In Chapter 2, I identify a necessary but not sufficient glycine residue conserved among propylating bacterial SMTs that occurs in the active site of SMT model structures. The presence of this glycine residue can therefore act as indicator of an SMT's ability to produce 24-isopropyl sterols. In Chapter 3,I find that bacterial SMTs are widely distributed in the environment but are particularly enriched in sponge metagenomes. Bacterial SMTs are actively transcribed in wastewater, soil, creeks, hot springs, and estuaries. Together, the results presented in this dissertation suggest bacteria may be an overlooked source of side-chain methylated sterols in the rock record, provide a framework for predicting SMT function directly from sequencing data, and highlight environments that can be targeted for future cultivation of bacteria that produce side-chain methylated sterols. Overall, this work demonstrates how techniques in molecular biology, biochemistry, and bioinformatics can be leveraged to improve the interpretation of molecular fossils.
590 $a School code: 0212.
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650 4 $a Fungi. $3 571472
650 4 $a Bioinformatics. $3 553671
650 4 $a Eukaryotes. $3 3695352
650 4 $a Biosynthesis. $3 516407
650 4 $a Bacteria. $3 550366
650 4 $a Labeling. $3 3560710
650 4 $a Cholesterol. $3 3382101
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650 4 $a Sterols. $3 915849
650 4 $a Genomes. $3 592593
650 4 $a Drinking water. $3 605014
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650 4 $a Chromatography. $3 1073639
650 4 $a Lipids. $3 558980
650 4 $a Creeks & streams. $3 3685269
650 4 $a Algae. $3 546231
650 4 $a Cloning. $3 571606
650 4 $a Steroids. $3 697464
650 4 $a Biomarkers. $3 2205735
650 4 $a Enzymes. $3 520899
650 4 $a Aquatic sciences. $3 3174300
650 4 $a Biochemistry. $3 518028
650 4 $a Genetics. $3 530508
650 4 $a Microbiology. $3 536250
650 4 $a Water resources management. $3 794747
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